Substituted thiophene- and furan-fused azolopyrimidine-5-(6H)-one compounds

ABSTRACT

Described herein are compounds and chemical entities of Formula (I), methods of their synthesis, compositions comprising them, and their use in treating numerous diseases and disorders, including cognitive deficits associated with CNS diseases and disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. For example, this application is a U.S. National Phase ofInternational Application No. PCT/US2013/046403, filed on Jun. 18, 2013designating the U.S. and published on Dec. 27, 2013 as WO 2013/192225,which claims the benefit of U.S. Provisional Application 61/661,091,filed on Jun. 18, 2012, which is incorporated herein by reference in itsentirety.

REFERENCE TO SEQUENCE LISTING

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is provided as a file entitledDNS.013NP.TXT, created Sep. 30, 2015, which is 4 kb in size. Theinformation in the electronic format of the Sequence Listing isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to certain substituted thiophene- andfuran-fused azolopyrimidin-5-(6h)-one compounds and derivatives of suchcompounds; pharmaceutical compositions containing them, methods ofmaking them, and their use in various methods, including the inhibitionof PDE1 enzymes; and the treatment of one or more disorders, includingneurological disorders, cardiovascular disorders, renal disorders, andother conditions and diseases involving PDE1 or cyclic nucleotidesignaling.

BACKGROUND OF THE INVENTION

The cyclic nucleotides 5′-3′ cyclic adenosine monophosphate (cAMP) and5′-3′ cyclic guanosine monophosphate (cGMP) are second messengermolecules, relaying signals from receptors on the cell surface to targetmolecules inside the cell. The cyclic nucleotide phosphodiesterases(PDEs) are a group of enzymes (which can be localized to differentcellular compartments) that hydrolyze the phosphodiester bond of cyclicnucleotides and thereby inactivate their function. PDEs can thereforeplay important roles in signal transduction by modulating thelocalization, amplitude, and duration of cyclic nucleotide signalingwithin the cell.

PDEs comprise at least eleven families: PDE1-PDE11, each categorized bydistinct molecular, kinetic, regulatory, and inhibitory properties. PDEfamily members are differentially expressed in various tissues and canlocalize to distinct sub-cellular domains. This diversity enables PDEsto modulate local intracellular cAMP and cGMP gradients in response todiscrete external stimuli (Conti and Beavo, Annu. Rev. Biochem. 2007,76, 481-511).

Among the PDE families, PDE1 is unique in its requirement for fullactivation by calcium (Ca²⁺) and calmodulin (CaM). Calcium enters thecell and forms a complex with CaM. Binding of the Ca²⁺/CaM complexes tomultiple domains near the N-terminus of PDE1 can result in fullphosphodiesterase activity. PDE1 is therefore a point of convergence andintegration for multiple signaling pathways that regulate numerousdownstream targets and cellular events (Sharma et al., Int. J. Mol. Med.2006, 18, 95-105).

The PDE1 family comprises three genes (pde1a, pde1b, and pde1c), andeach encodes multiple isoforms via alternative splicing and differentialtranscription. All PDE1 enzymes appear to hydrolyze both cAMP and cGMP,although they can differ in their relative affinities for each (Benderand Beavo, Pharmacol. Rev. 2006, 58, 488-520).

PDE1 is expressed in many tissues, underscoring a role in manyphysiological processes. Regions of PDE expression include, but are notlimited to, the heart, lungs, veins and arteries, smooth muscle,skeletal muscle, skin, adrenal gland, thyroid, pancreas, esophagus,stomach, small intestine, colon, liver, leukocytes, testis, ovary,bladder, kidney, and the nervous system. In the brain, PDE1 isoforms areexpressed in the cerebral cortex, frontal lobe, hippocampus, cerebellum,and amygdala, regions involved in memory formation and other cognitiveprocesses. PDE1b expression, in particular, correlates closely withbrain regions showing high levels of dopaminergic innervation. In thecardiovascular system, PDE1 appears to play a central role in organizingcAMP microdomains and mediating hormonal specificity in cardiac cells(Maurice et al., Mol. Pharm. 2003, 64, 533-546). Indeed, human PDE1b ishighly expressed in numerous cardiovascular regions, including thepericardium, heart atrium (left), heart apex, Purkinje fibers, andpulmonic valve.

More generally, cyclic nucleotide signaling pathways, including thoseinvolving PDE1, are implicated in numerous pathological processes(Keravis and Lugnier, Br. J. Pharmacol. 2012, 165, 1288-1305). Forexample, alterations in these pathways have been implicated in variousdisorders of the brain, including depression, schizophrenia andcognitive disorders. Inhibiting PDE1 activity in the nervous system, forexample, can increase cAMP or cGMP levels and consequently induceexpression of neuronal plasticity-related genes, neurotrophic factors,and neuroprotective molecules. Based on such properties, PDE1 inhibitorsare promising therapeutic candidates in treating many CNS disorders andassociated cognitive impairments. Similarly, PDE1 enzymes and cyclicnucleotides are emerging as key mediators of pathological processes thatunderlie many vascular disorders, including hypertension, myocardialinfarction, and heart failure (Miller et al., Basic Res. Cardiol. 2011,106, 1023-1039 and Miller et al, Circ. Res. 2009, 105, 956-964). Inaddition, PDE1 is implicated in the development and progression of renaldisease, where cAMP and cGMP regulate a variety of signaling pathways,including those that modulate mitogenesis, inflammation, andextracellular matrix synthesis (Wang et al., Kidney Int. 2010, 77.129-140; Cheng et al., Soc. Exp. Biol. Med. 2007, 232, 38-51 and Dousa,Kidney Int. 1999, 55, 29-62).

Accordingly, there is a need to develop treatments for CNS and otherdisorders, as well as disorders that are due, at least in part, to anaberration or dysregulation of an intracellular signaling pathwayregulated by PDE1.

Various small-molecule PDE1 enzyme inhibitors have been reported e.g.,imidazopyrazolopyrimidinones (Intra-Cellular Therapeutics Intl. Pat.Appl. Publ. WO 2012171016, Dec. 13, 2012), pyrrolopyrimidinones(Intra-Cellular Therapeutics Intl. Pat. Appl. Publ. WO 2011153138, Dec.8, 2011; Intl. Pat. Appl. Publ. WO 2011153136, Dec. 8, 2011; Intl. Pat.Appl. Publ. WO 2011153135, Dec. 8, 2011; Intl. Pat. Appl. Publ. WO2011153129, Dec. 8, 2011), imidazopurinone (Intra-Cellular TherapeuticsIntl. Pat. Appl. Publ. WO 2010132127, Nov. 18, 2010),pyrazolopyrimidinedione (Intra-Cellular Therapeutics Intl. Pat. Appl.Publ. WO 2010098839, Sep. 2, 2010), pyrazolopyrimidinone (Intra-CellularTherapeutics Intl. Pat. Appl. Publ. WO 2010065153, Jun. 10, 2010; WO2010065149, Jun. 10, 2010; Intl. Pat. Appl. Publ. WO 2009075784, Jun.18, 2009).

However, there remains a need for potent PDE1 inhibitors with desirablepharmaceutical properties. It is therefore desirable to develop improvedPDE1 inhibitors showing higher potency, greater specificity, and betterside effect profiles. The present invention meets these and other needsin the art by disclosing substituted thiophene and furan fusedazolopyrimidin-5-(6h)-one compounds as potent and well-tolerated PDE1inhibitors.

SUMMARY OF THE INVENTION

The invention provides a chemical entity of Formula (I):

whereinR¹, R³, R⁴, X, Y and M have any of the values described herein.

In one aspect the chemical entity is selected from the group consistingof compounds of Formula (I), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically acceptable metabolites ofcompounds of Formula (I). In a specific aspect, the chemical entity is acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

Chemical entities and compounds of Formula (I) are useful in wide rangeof methods. Isotopically-labeled compounds and prodrugs can be used inmetabolic and reaction kinetic studies, detection and imagingtechniques, and radioactive treatments. The chemical embodiments of thepresent invention can be used to inhibit PDE1, and PDE1b, in particular;to treat a disorder mediated by PDE1, and PDE1b, in particular; toenhance neuronal plasticity; to treat neurological disorders, includingneurodegenerative disorders, cognitive disorders, and cognitive deficitsassociated with CNS disorders; to confer neuroprotection; and to treatperipheral disorders, including obesity, diabetes, cardiometabolicdisorders, and their associated co-morbidities. The chemical embodimentsof the present invention are also useful as augmenting agents to enhancethe efficiency of cognitive and motor training, to facilitateneurorecovery and neurorehabilitation, and to increase the efficiency ofnon-human animal training protocols. The invention is further directedto the general and specific embodiments defined, respectively, by theindependent and dependent claims appended hereto, which are incorporatedby reference herein.

The invention further relates to the use of a compound, chemical entity,or composition of the instant invention in a method of treatingdisorders that include an aberrant or dysregulated signaling pathwaymediated by PDE1, and more specifically, PDE1b. Such PDE1-relatedsignaling pathways, preferably in the nervous system, include, but arenot limited to, those involving nitric oxide, natriuretic peptides,dopamine, noradrenalin, neurotensin, cholecystokinin, vasoactiveintestinal peptide, serotonin, glutamate, GABA, acetylcholine,adenosine, cannabinoids, natriuretic peptides, and endorphins. In aspecific aspect, the compounds and compositions are useful in treatingdisorders characterized by alterations in dopamine signaling.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is bar graph showing the effect of siRNA-mediated knockdown ofPDE1b in mouse hippocampal tissue on one-day memory in a contextualfear-conditioning assay.

FIG. 2 is a bar graph showing the effect of siRNA-mediated knockdown ofPDE1b in mouse hippocampal tissue on one-day memory in atrace-conditioning assay.

FIG. 3 is a bar graph showing the effect on neurite outgrowth of (A)rolipram-mediated inhibition of PDE4, and (B) siRNA-mediated inhibitionof Pde4d or Pde1b. Bars represent the mean±SEM of neurite length andbranching of at least 100 NS1 cells; n=8 wells/bar.

DETAILED DESCRIPTION OF THE INVENTION

The invention may be more fully appreciated by reference to thefollowing description, including the examples. Unless otherwise defined,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art. Althoughmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of the present invention,suitable methods and materials are described herein. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

For the sake of brevity, all publications, including patentapplications, patents, and other citations mentioned herein, areincorporated by reference in their entirety. Citation of any suchpublication, however, shall not be construed as an admission that it isprior art to the present invention.

ABBREVIATIONS

The specification includes numerous abbreviations, whose meanings arelisted in the following Table:

Abbreviation Definition ACN Acetonitrile BINAP2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl BOC tert-butoxycarbonyl BOCanhydride Di-tert-butyl dicarbonate CELITE ® Diatomaceous earth m-CPBAmeta-Chloroperoxybenzoic acid DAST Diethylaminosulfur trifluoride DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCE Dichloroethane DCMDichloromethane Diglyme (2-Methoxyethyl) ether DIPEAN,N-ethyl-diisopropylamine or N,N-Diisopropyl-ethyl amine DMAN,N-Dimethylacetamide DMAP 4-Dimethylamino pyridine DME DimethoxyethaneDMF N,N-Dimethylformamide DMSO Dimethylsulfoxide dppf1,1′-Bis(diphenylphosphino)ferrocene EDCIN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride EtOAc, orEA Ethyl Acetate EtOH Ethanol IPA Isopropyl alcohol HOAc or AcOH AceticAcid HOAT 1-Hydroxy-7-azabenzotriazole HPLC High-performance liquidchromatography KHMDS Potassium bis(trimethylsilyl)amide LAH Lithiumaluminum hydride LiHMDS, Lithium bis(trimethylsilyl)amide LCMS, LC/MSLiquid chromatography-mass spectrometry MeOH Methanol MsCIMethanesulfonyl chloride MTBE Methyl tert-butyl ether NMP1-Methyl-2-pyrrolidinone Pd/C Palladium on activated carbon Pd₂(dba)₃Tris(dibenzylideneacetone)dipalladium (0) PdCl₂(dppf)-dcm[1′1′-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride Pd(OAc)₂Palladium(II)acetate Pd(PPh₃)₄ Palladium-tetrakis(triphenylphosphine)TEA, Et₃N Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran

TERMS AND DEFINITIONS

The use of subheadings such as “General,” “Chemistry,” “Compositions,”Formulations,” etc., in this section, as well as in other sections ofthis application, are solely for convenience of reference and notintended to be limiting.

General

As used herein, the term “about” or “approximately” means within anacceptable range for a particular value as determined by one skilled inthe art, and may depend in part on how the value is measured ordetermined, e.g., the limitations of the measurement system ortechnique. For example, “about” can mean a range of up to 20%, up to10%, up to 5%, or up to 1% or less on either side of a given value.Alternatively, with respect to biological systems or processes, the term“about” can mean within an order of magnitude, within 5-fold, or within2-fold on either side of a value. Numerical quantities given herein areapproximate unless stated otherwise, meaning that the term “about” or“approximately” can be inferred when not expressly stated

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation of such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity for which that could be obtained under the particularstoichiometric conditions. Concentrations that are given as percentagesrefer to mass ratios, unless indicated differently.

As used herein, the terms “a,” “an,” and “the” are to be understood asmeaning both singular and plural, unless explicitly stated otherwise.Thus, “a,” “an,” and “the” (and grammatical variations thereof whereappropriate) refer to one or more.

A group of items linked with the conjunction “and” should not be read asrequiring that each and every one of those items be present in thegrouping, but rather should be read as “and/or” unless expressly statedotherwise. Similarly, a group of items linked with the conjunction “or”should not be read as requiring mutual exclusivity among that group, butrather should also be read as “and/or” unless expressly statedotherwise. Furthermore, although items, elements or components of theinvention may be described or claimed in the singular, the plural iscontemplated to be within the scope thereof, unless limitation to thesingular is explicitly stated.

The terms “comprising” and “including” are used herein in their open,non-limiting sense. Other terms and phrases used in this document, andvariations thereof, unless otherwise expressly stated, should beconstrued as open ended, as opposed to limiting. As examples of theforegoing: the term “example” is used to provide exemplary instances ofthe item in discussion, not an exhaustive or limiting list thereof;adjectives such as “conventional,” “traditional,” “normal,” “criterion,”“known” and terms of similar meaning should not be construed as limitingthe item described to a given time period or to an item available as ofa given time, but instead should be read to encompass conventional,traditional, normal, or criterion technologies that may be available orknown now or at any time in the future. Likewise, where this documentrefers to technologies that would be apparent or known to one ofordinary skill in the art, such technologies encompass those apparent orknown to the skilled artisan now or at any time in the future.

The presence of broadening words and phrases such as “one or more,” “atleast,” “but not limited to” or other like phrases in some instancesshall not be read to mean that the narrower case is intended or requiredin instances where such broadening phrases may be absent. As will becomeapparent to one of ordinary skill in the art after reading thisdocument, the illustrated embodiments and their various alternatives maybe implemented without confinement to the illustrated examples.

Chemistry

The term “alkyl” refers to a fully saturated aliphatic hydrocarbongroup. The alkyl moiety may be a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude, but are not limited to, methyl (Me, which also may bestructurally depicted by the symbol, “

”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl,ten-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, andgroups that in light of the ordinary skill in the art and the teachingsprovided herein would be considered equivalent to any one of theforegoing examples. Alkyl groups may be optionally substituted with oneor more substituents including, but not limited to, hydroxyl, alkoxy,thioalkoxy, amino, and aminoalkyl.

The term “alkenyl” refers to optionally substituted unsaturatedaliphatic moieties having at least one carbon-carbon double bond andincluding E and Z isomers of said alkenyl moiety. Examples of alkenylradicals include ethenyl, propenyl, butenyl, 1,4-butadienyl,cyclopentenyl, cyclohexenyl and the like.

The term “alkynyl” refers to an optionally substituted unsaturatedaliphatic moieties having at least one carbon-carbon triple bond andincludes straight and branched chain alkynyl groups. Examples of alkynylradicals include ethynyl, propynyl, butynyl and the like.

The term “haloalkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain optionally substitutinghydrogens with halogens. Examples of haloalkyl groups include, but arenot limited to, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CF₂CF₃ and other groups that in light of the ordinaryskill in the art and the teachings provided herein, would be consideredequivalent to any one of the foregoing examples.

The term “alkoxy” includes a straight chain or branched alkyl group withan oxygen atom linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on. “Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” areanalogous to alkoxy, replacing the terminal oxygen atom of alkoxy with,respectively, NH (or NR), S, and SO₂.

The term “haloalkoxy” refer to alkoxy groups optionally substitutinghydrogens with halogens. Examples of haloalkoxy groups include, but arenot limited to, —OCF₃, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂Cl, —OCH₂CF₂CF₃ andother groups that in light of the ordinary skill in the art and theteachings provided herein, would be considered equivalent to any one ofthe foregoing examples.

The term “amino” refers to the —NH₂ group.

The term “alkylamino” refers to the —NRR′ group, where R and R′ areindependently selected from hydrogen (however, R and R′ cannot both behydrogen), alkyl, and aryl groups; or R and R′, taken together, can forma cyclic ring system. Examples of amino groups include, but are notlimited to, —NH(CH₃), —N(CH₃)₂, —NPhenyl(CH₃), —NHPhenyl,—N(CH₂CH₃)(CH₃), and the like.

The term “cyano” refers to the group —CN.

The term “aryl” refers to a monocyclic, or fused or spiro polycyclic,aromatic carbocycle (ring structure having ring atoms that are allcarbon), having from 3 to 12 ring atoms per ring. (Carbon atoms in arylgroups are sp2 hybridized.) Illustrative examples of aryl groups includethe following moieties:

and the like.

The term “aryloxy” refers to a group having the formula, —O—R, wherein Ris an aryl group.

The term “cycloalkyl” refers to a saturated or partially saturatedcarbocycle, such as monocyclic, fused polycyclic, bridged monocyclic,bridged polycyclic, spirocyclic, or spiro polycyclic carbocycle havingfrom 3 to 12 ring atoms per carbocycle. Where the term cycloalkyl isqualified by a specific characterization, such as monocyclic, fusedpolycyclic, bridged polycyclic, spirocyclic, and spiro polycyclic, thensuch term cycloalkyl refers only to the carbocycle so characterized.Illustrative examples of cycloalkyl groups include the followingentities, in the form of properly bonded moieties:

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Illustrative entities, in the form ofproperly bonded moieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkyl,heterocycloalkyl, and heteroaryl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “heteroatom” used herein refers to, for example, O (oxygen), S(sulfur), or N (nitrogen).

The term “substituted” means that the specified group or moiety bearsone or more substituents. Where the term “substituted” is used todescribe a structural system, unless specified otherwise, thesubstitution is meant to occur at any valency-allowed position on thesystem. The term “unsubstituted” means that the specified group bears nosubstituents. The term “optionally substituted” means that the specifiedgroup is unsubstituted or substituted with one or more additionalsubstitutents individually and independently selected from the groupcomprising: cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —CN, —OH,—NO₂, —SO₂NH₂, —CONH₂, —CO₂H, —COH, amino, —(C₁₋₆ alkyl)amino,di(C₁₋₆alkyl)amino, —N3, cyanate, isocyanate, thiocyanate,isothiocyanate, aryloxy, and arylthio. In cases where a specified moietyor group is not expressly noted as being optionally substituted orsubstituted with any specified substituent, it is understood that such amoiety or group is intended to be unsubstituted.

Formulas

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.

The symbols

and

are used as meaning the same spacial arrangement in chemical structuresshown herein. Analogously, the symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein.

Compounds

As used herein, a “compound” refers to any one of: (a) the actuallyrecited form of such compound; and (b) any of the forms of such compoundin the medium in which the compound is being considered when named. Forexample, reference herein to a compound such as R—COOH, encompassesreference to any one of, for example, R—COOH(s), R—COOH(sol), andR—COO-(sol). In this example, R—COOH(s) refers to the solid compound, asit could be for example in a tablet or some other solid pharmaceuticalcomposition or preparation; R—COOH(sol) refers to the undissociated formof the compound in a solvent; and R—COO-(sol) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO— upon dissociation in the medium being considered.

As used herein, the term “chemical entity” collectively refers to acompound, along with the derivatives of the compound, including salts,chelates, solvates, conformers, non-covalent complexes, metabolites, andprodrugs.

In one aspect the chemical entity is selected from the group consistingof compounds of Formula (I), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically acceptable metabolites ofcompounds of Formula (I). In a specific aspect, the chemical entity is acompound of Formula (I), or a pharmaceutically acceptable salt.

In another example, an expression such as “exposing an entity to acompound of formula R—COOH” refers to the exposure of such entity to theform, or forms, of the compound R—COOH that exists, or exist, in themedium in which such exposure takes place. In still another example, anexpression such as “reacting an entity with a compound of formulaR—COOH” refers to the reacting of (a) such entity in the chemicallyrelevant form, or forms, of such entity that exists, or exist, in themedium in which such reacting takes place, with (b) the chemicallyrelevant form, or forms, of the compound R—COOH that exists, or exist,in the medium in which such reacting takes place. In this regard, ifsuch entity is for example in an aqueous environment, it is understoodthat the compound R—COOH is in such same medium, and therefore theentity is being exposed to species such as R—COOH(aq) and/or R—COO-(aq),where the subscript “(aq)” stands for “aqueous” according to itsconventional meaning in chemistry and biochemistry. A carboxylic acidfunctional group has been chosen in these nomenclature examples; thischoice is not intended, however, as a limitation but it is merely anillustration. It is understood that analogous examples can be providedin terms of other functional groups, including but not limited tohydroxyl, basic nitrogen members, such as those in amines, and any othergroup that interacts or transforms according to known manners in themedium that contains the compound. Such interactions and transformationsinclude, but are not limited to, dissociation, association, tautomerism,solvolysis, including hydrolysis, solvation, including hydration,protonation and deprotonation. No further examples in this regard areprovided herein because these interactions and transformations in agiven medium are known by any one of ordinary skill in the art.

In another example, a “zwitterionic” compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. As isgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion +H₃NCH₂COO—. Zwitterions, zwitterionic compounds,inner salts, and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Isotopes may be present in the compounds described. Each chemicalelement present in a compound either specifically or genericallydescribed herein may include any isotope of said element. Any formulagiven herein is also intended to represent isotopically labeled forms ofthe compounds. Isotopically labeled compounds have structures depictedby the formulas given herein except that one or more atoms are replacedby an atom having a selected atomic mass or mass number. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of species for the same variable elsewherein the formula, unless otherwise stated.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂ and “S² _(example) is one of S₃ and S₄ isaccordingly used herein for the sake of brevity but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, D, M, X, and Y andany other generic substituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂ and S₃, the listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S²; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂ and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, D, M, X, and Y andany other generic substituent symbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with the total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B—, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the second memberand B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

The term “prodrug” means a precursor of a designated compound that,following administration to a subject, yields the compound in vivo via achemical or physiological process such as solvolysis or enzymaticcleavage, or under physiological conditions (e.g., a prodrug on beingbrought to physiological pH is converted to the compound of Formula(I)).

A “pharmaceutically acceptable prodrug” is a prodrug that is preferablynon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to the subject. Illustrative procedures for theselection and preparation of suitable prodrug derivatives are described,for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

A “metabolite” means a pharmacologically active product of metabolism inthe body of a compound of Formula (I) or salt thereof. Preferably, themetabolite is in an isolated form outside the body.

Compositions

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) (pharmaceutically acceptable excipients) that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation, or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula (I) and a pharmaceutically acceptable excipient.

The term “pharmaceutically acceptable,” as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to ananimal (e.g., human). The term “pharmaceutically acceptable” may alsomean approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals (e.g. mammals), and moreparticularly in humans.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluents to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols. Suitablepharmaceutical carriers include those described in Remington: TheScience and Practice of Pharmacy, 21^(st) Ed., Lippincott Williams &Wilkins (2005).

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G. S. Paulekuhn etal., Trends in Active Pharmaceutical Ingredient Salt Selection based onAnalysis of the Orange Book Database, J. Med. Chem. 2007, 50, 6665-6672;Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977, 66, 1-19; Stahland Wermuth (eds), Pharmaceutical Salts; Properties, Selection, and Use:2nd Revised Edition, Wiley-VCS, Zurich, Switzerland (2011). Examples ofpharmaceutically acceptable salts are those that are pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. A compound of Formula(I) may possess a sufficiently acidic group, a sufficiently basic group,or both types of functional groups, and accordingly react with a numberof inorganic or organic bases, and inorganic and organic acids, to forma pharmaceutically acceptable salt bases, and inorganic and organicacids, to form a pharmaceutically acceptable salt.

The term “carrier” refers to an adjuvant, vehicle, or excipients, withwhich the compound is administered. In preferred embodiments of thisinvention, the carrier is a solid carrier. Suitable pharmaceuticalcarriers include those described in Remington: The Science and Practiceof Pharmacy, 21^(st) Ed., Lippincott Williams & Wilkins (2005).

The term “dosage form,” as used herein, is the form in which the dose isto be administered to the subject or patient. The drug is generallyadministered as part of a formulation that includes nonmedical agents.The dosage form has unique physical and pharmaceutical characteristics.Dosage forms, for example, may be solid, liquid or gaseous. “Dosageforms” may include for example, a capsule, tablet, caplet, gel caplet(gelcap), syrup, a liquid composition, a powder, a concentrated powder,a concentrated powder admixed with a liquid, a chewable form, aswallowable form, a dissolvable form, an effervescent, a granulatedform, and an oral liquid solution. In a specific embodiment, the dosageform is a solid dosage form, and more specifically, comprises a tabletor capsule.

As used herein, the term “inert” refer to any inactive ingredient of adescribed composition. The definition of “inactive ingredient” as usedherein follows that of the U.S. Food and Drug Administration, as definedin 21 C.F.R. 201.3(b)(8), which is any component of a drug product otherthan the active ingredient.

Methods and Uses

As used herein, the term “disorder” is used interchangeably with“disease” or “condition”. For example, a CNS disorder also means a CNSdisease or a CNS condition.

As used herein, the term “cognitive impairment” is used interchangeablywith “cognitive dysfunction” or “cognitive deficit,” all of which aredeemed to cover the same therapeutic indications.

The term “treat,” as used herein, is interchangeable with “treatment”and “treating” and includes:

-   -   (i) prevention of the disease, disorder, or condition, i.e.,        reducing the incidence of and/or ameliorating the effect and/or        duration of a disease, disorder, or condition from occurring in        subjects that may get, be exposed to and/or be predisposed to        the disease, disorder or condition, but may not yet have been        diagnosed as having it; or are diagnosed as having the disease,        disease, or condition; or are at risk of developing such        disease, disorder, or condition;    -   (ii) inhibition of the disease, disorder, or condition, i.e.,        preventing or delaying the onset of a disease, disorder, or        condition; arresting further development or progression of a        disease, disorder, or condition in a subject already suffering        from or having one or more symptoms of the disease, disorder, or        condition; or reducing the risk of a disease, disorder, or        condition worsening;    -   (iii) amelioration of the disease, disorder, or condition, i.e.,        attenuating, relieving, reversing or eliminating the disease,        disorder, or condition, or one or more of symptoms thereof.

As used in the present disclosure, the term “effective amount” isinterchangeable with “therapeutically effective amount” and means anamount or dose of a compound or composition effective in treating theparticular disease, condition, or disorder disclosed herein, and thus“treating” includes producing a desired preventative, inhibitory,relieving, or ameliorative effect. In methods of treatment according tothe invention, “an effective amount” of at least one compound accordingto the invention is administered to a subject (e.g., a mammal).

The term “animal” is interchangeable with “subject” and may be avertebrate, in particular, a mammal, and more particularly, a human, andincludes a laboratory animal in the context of a clinical trial orscreening or activity experiment. Thus, as can be readily understood byone of ordinary skill in the art, the compositions and methods of thepresent invention are particularly suited to administration to anyvertebrate, particularly a mammal, and more particularly, a human.

As used herein, a “control animal” or a “normal animal” is an animalthat is of the same species as, and otherwise comparable to (e.g.,similar age, sex), the animal that is trained under conditionssufficient to induce transcription-dependent memory formation in thatanimal.

By “enhance,” “enhancing,” or “enhancement” is meant the ability topotentiate, increase, improve or make greater or better, relative tonormal, a biochemical or physiological action or effect. For example,enhancing long term memory formation refers to the ability to potentiateor increase long term memory formation in an animal relative to thenormal long term memory formation of the animal or controls. As aresult, long term memory acquisition is faster or better retained.Enhancing performance of a cognitive task refers to the ability topotentiate or improve performance of a specified cognitive task by ananimal relative to the normal performance of the cognitive task by theanimal or controls.

As used herein, the term “training protocol,” or “training,” refers toeither “cognitive training” or “motor training.” The phrase “inconjunction” means that a compound or composition of the presentinvention enhances CREB pathway function during cognitive or motortraining.

Reference will now be made to the embodiments of the present invention,examples of which are illustrated by and described in conjunction withthe accompanying drawings and examples. While certain embodiments aredescribed herein, it is understood that the described embodiments arenot intended to limit the scope of the invention. On the contrary, thepresent disclosure is intended to cover alternatives, modifications, andequivalents that can be included within the invention as defined by theappended claims.

Compounds

The present invention provides certain substituted thiophene and furanfused azolopyrimidin-5-(6h)-one derivatives, which are useful, forexample, as inhibitors of PDE1 enzymatic activity. They are distinctfrom substituted azolopyrimidin-5-(6h)-ones in US Pat. App.US20090163545 (University of Rochester, CAS No. 838843-34-8, Jun. 2,2009).

In its many embodiments, the invention is directed to a chemical entityof Formula (I):

wherein:

-   X is —CH— or —N—;-   Y is —O— or —S—;-   M is 0-5;-   R¹ is each independently selected from the group consisting of: H,    halo, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₁₋₆thioalkyl, —C₁₋₆alkoxy,    —C₁₋₆haloalkoxy, —SO₂C₁₋₆alkyl, aryl, heteroaryl, and    heterocycloalkyl;-   R³ and R⁴ are each independently selected from the group consisting    of —H, halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —CH₂OH, —C₁₋₆alkoxy,    —C₁₋₆haloalkoxy, aryl, optionally substituted 5 or 6 membered    heteroaryl, —(C₁-C₆alkyl)aryl, —(C₁-C₆ alkyl)heteroaryl, and    —(CR¹⁰R¹¹)₁₋₃NR¹²R¹³;    or R³ and R⁴ taken together with the carbons to which they are    attached form a saturated or unsaturated monocylic ring system,    having the following structure:

-   D is —O—, —N(R⁹)—, or a bond;-   m and n are each independently 0-4, with the proviso that the sum of    m and n is 1-5 when D is —O—, —N(R⁹)—, or is 2-6 when D is a bond;-   R⁵, R⁶, R⁷, R⁸, are each independently selected from the group    consisting of: —H, —F, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —OH, —C₁₋₆alkoxy,    —C₁₋₆haloalkoxy;-   R⁹ is selected from the group consisting of: —H, —C₁₋₆alkyl,    —C₁₋₆thioalkyl, —C₁₋₆haloalkyl, —CO₂C₁₋₆alkyl, —SO₂(C₁₋₆alkyl),    —C₁₋₆alkyl(aryl), —C₁₋₆alkyl(C₃₋₆cycloalkyl),    —C₁₋₆alkyl(heterocycloalkyl), —C₁₋₆alkyl(heteroaryl), heteroaryl,    —CO(aryl), —CO(heteroaryl), —CO(heterocycloalkyl),    —CO(C₃₋₆cycloalkyl), wherein each aryl, cycloalkyl,    heterocycloalkyl, heteroaryl are optionally unsubstituted or    substituted with a member each independently selected from the group    consisting of —H, —Cl, —F, and —CH₃;-   R¹⁰ and R¹¹ are each independently selected from the group    consisting of: —H, —F, —C₁₋₆alkyl, —CF₃, and —OH;-   R¹² and R¹³ are each independently selected from the group    consisting of: —H, —C₁₋₆ alkyl, —C₃₋₆cycloalkyl, —C₁₋₆alkyl(aryl),    —C₁₋₆alkyl(heteroaryl), —C₁₋₆alkyl(heterocycloalkyl),    —CH₂CON(C₁₋₆alkyl)₂;-   or R¹² and R¹³ are taken together with the nitrogen to which they    are attached form a heterocycloalkyl ring, optionally substituted    with one or more R¹⁴, where each R¹⁴ is independently selected from    the group consisting of: —H, —C₁₋₆alkyl, —CH₂OH, —OH, —COCH₃,    —SO₂CH₃, —O-pyridyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,    —O— phenyl, —O-(2-fluorophenyl), -morpholino,    1,1-difluoro-cyclopropyl, or two R¹⁴ members are taken together to    form a —C₃₋₆heterocycloalkyl.

In some embodiments, the chemical entity is selected from the groupconsisting of compounds of Formula (I), pharmaceutically acceptablesalts of compounds of Formula (I), pharmaceutically acceptable prodrugsof compounds of Formula (I); and pharmaceutically active metabolites ofcompounds of Formula (I). In a particular aspect, the chemical entity isa compound, or pharmaceutically acceptable salt thereof, of Formula (I).

In certain embodiments, m and n are each independently 0-4, with theproviso that the sum of m and n is 1-5 when D is —O—, —N(R⁹)—, or is 2-6when D is a bond; and with the further proviso that when D is a bond, R¹is not —Cl in the para position.

In certain embodiments, of Formula (I), X is —N—.

In certain embodiments, of Formula (I), X is —CH—.

In certain embodiments, of Formula (I), Y is —S—.

In certain embodiments, of Formula (I), Y is —O—.

Some embodiments are given by compounds of Formula (I) where M is 1, 2,3, 4, or 5.

Some embodiments are given by compounds of Formula (I) where M is 1, 2,3 or 4.

Some embodiments are given by compounds of Formula (I) where M is 1, 2or 3.

In certain embodiments, of Formula (I), M is 1, 2 or 3 and R¹ is eachindependently halo or —C₁₋₆alkoxy.

In some of these embodiments, R¹ is —OCH₃.

In some of these embodiments, R¹ is —F, —Cl, —Br, —CF₃, —CN or —CHF₂.

Some embodiments are given by compounds of Formula (I) where R³ is H,—Br, —C₁₋₆alkyl, benzyl, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yland R⁴ is H or —CH₃.

Some embodiments are given by compounds of Formula (I) where R³ is—(CR¹⁰R¹¹)₁₋₃NR¹²R¹³ and R⁴ is H or —CH₃.

In certain embodiments of Formula (I), R³ is H, —Br, —C₁₋₅alkyl, benzyl,1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, or —(CR¹⁰R¹¹)NR¹²R¹³,where R¹⁰ and R¹¹ are each H, R¹² is H or —C₁₋₆alkyl, R¹³ is —CH₃,—CH₂CON(CH₃)₂, cyclopropyl, benzyl, 3-pyridyl, oxan-4-ylmethyl,2,2-dimethyloxan-4-yl, (3-methyloxetan-3-yl)methyl,(tetrahydrofuran-2-yl)methyl or (tetrahydrofuran-3-yl)methyl and R⁴ is Hor —CH₃.

In certain embodiments of Formula (I), R³ is —(CR¹⁰R¹¹)NR¹²R¹³, whereR¹⁰ and R¹¹ are each H, R¹² is H, —C₁₋₆alkyl, R¹³ is —CH₃,—CH₂CON(CH₃)₂, cyclopropyl, benzyl, 3-pyridyl,(tetrahydrofuran-2-yl)methyl, (tetrahydrofuran-3-yl)methyl,oxan-4-ylmethyl, 2,2-dimethyloxan-4-yl or (3-methyloxetan-3-yl)methyland R⁴ is H or —CH₃.

Some embodiments are given by compounds of Formula (I) where R³ is H or—CH₃ and R⁴ is —(CR¹⁰R¹¹)₁₋₃NR¹²R¹³.

In some of these embodiments, H or —CH₃, R⁴ is —(CR¹⁰R¹¹)NR¹²R¹³, whereR¹⁰ and R¹¹ are each H, R¹² is H or —C₁₋₆alkyl, and R¹³ is —C₁₋₆alkyl oroxan-4-ylmethyl.

Some embodiments are given by compounds of Formula (I) where R³ or R⁴ is—(CR¹⁰R¹¹)₁₋₃NR¹²R¹³, R¹⁰ and R¹¹ are each independently H, —CH₃, or—OH, and R¹² and R¹³ are taken together with the nitrogen to which theyare attached to form a heterocycloalkyl ring selected from(2R,6S)-2,6-dimethylmorpholine, (2S,6R)-2,6-dimethylmorpholine,(3R,5S)-3,5-dimethylpiperazine, 1,1-difluoro-5-azaspiro[2.4]heptane,1,4-oxazepane, 2-(methoxymethyl)pyrrolidine, 2,2-dimethylmorpholine,2,6-dimethylmorpholine, 2-ethylmorpholine, 2-methylmorpholine,2-oxa-5-azabicyclo[2.2.1]heptane, 3-(2-fluorophenoxy)azetidine,3,3,4-trimethylpiperazine, 3,4-dimethylpiperazine, 3-hydroxyazetidine,3-methylmorpholine, 3-oxopiperazine, 4-(2-fluorophenyl)piperazine,4-(3-fluorophenyl)piperazine, 4-(4-fluorophenyl)piperazine,4-(methylsulfonyl)piperazine, 4-(morpholin-4-yl)piperidine,4-(pyridin-4-yloxy)piperidine, 4-acetyl-1,4-diazepane,4-acetylpiperazine, 4-ethyl-3-oxopiperazine, 4-hydroxypiperidine,4-isopropylpiperazine, 4-methyl-piperazine, 4-thiomorpholine-1,1-dione,8-oxa-3-azabicyclo[3.2.1]octane, isoindoline, morpholine,octahydropyrrolo[1,2-a]pyrazine, piperazine, and pyrrolidine.

Some embodiments are given by compounds of Formula (I) where R³ is((2R,6S)-2,6-dimethylmorpholin-4-yl)methyl,((2S,6R)-2,6-dimethylmorpholin-4-yl)methyl, (1,4-oxazepan-4-yl)methyl,(1,4-oxazepan-4-ylmethyl), (2,2-dimethylmorpholino)methyl,(3-hydroxyazetidin-1-yl)methyl,(4-(methylsulfonyl)piperazin-1-yl)methyl,(4-acetyl-1,4-diazepan-1-yl)methyl, (4-acetylpiperazin-1-yl)methyl,(4-ethyl-3-oxopiperazin-1-yl)methyl, (4-methylpiperazin-1-yl)methyl,[3-(2-fluorophenoxy)azetidin-1-yl]methyl,[4-(2-fluorophenyl)piperazin-1-yl]methyl,[4-(3-fluorophenyl)piperazin-1-yl]methyl,[4-(4-fluorophenyl)piperazin-1-yl]methyl,[4-(morpholin-4-yl)piperidin-1-yl]methyl,[4-(pyridin-4-yloxy)piperidin-1-yl]methyl,{1,1-difluoro-5-azaspiro[2.4]heptan-5-yl}methyl,2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl, 4-thiomorpholine-1,1-dione,7-oxa-2-azaspiro[3.5]nonan-2-ylmethyl, morpholinomethyl, and R⁴ is H,—CH₃.

In some of these embodiments, R³ is morpholinomethyl,(2,2-dimethylmorpholino)methyl, 2,6-dimethylmorpholino)methyl,((2S,6R)-2,6-dimethylmorpholino)methyl,((2R,6S)-2,6-dimethylmorpholin-4-yl)methyl,(4-(methylsulfonyl)piperazin-1-yl)methyl, 1-hydroxy-2-morpholinoethyl,2-((2S,6R)-2,6-dimethylmorpholino)-1-hydroxyethyl, R⁴ is H, —CH₃.

In certain embodiments of Formula (I), R⁴ is((2S,6R)-2,6-dimethylmorpholino)methyl,((2R,6S)-2,6-dimethylmorpholin-4-yl)methyl,[(3-phenoxypyrrolidin-1-yl)methyl],[3-(hydroxymethyl)-3-(2-methylpropyl)piperidin-1-yl]methyl,[ethyl(oxan-4-ylmethyl)amino]methyl,[methyl(oxan-4-ylmethyl)amino]methyl, [(oxan-4-ylmethyl)amino]methyl, or[bis(propan-2-yl)amino]methyl.

In certain embodiments of Formula (I), R³ and R⁴ taken together with thecarbons to which they are attached form a six member monocyclic ringsystem, wherein D is —O—, and m is 1 and n is 2.

In certain embodiments of Formula (I), R³ and R⁴ taken together with thecarbons to which they are attached form a six member monocyclic ringsystem, wherein D is —N(R⁹)—, and m is 0, 1, or 2 and n is 1, 2 or 3;with the proviso that the sum of m and n is 1-5.

In certain embodiments of Formula (I), R³ and R⁴ taken together with thecarbons to which they are attached form a six member monocyclic ringsystem, wherein D is a bond and m and n are 2.

Some embodiments are given by compounds of Formula (I) where R⁵, R⁶, R⁷,R⁸, are each independently —H, —F, or —CH₃.

Some embodiments are given by compounds of Formula (I) where R³ and R⁴taken together with the carbons to which they are attached form a sixmember monocyclic ring system, wherein D is —N(R⁹)—, and R⁹ is H,—C₁₋₆alkyl, —C₁₋₆haloalkyl, —SO₂CH₃, benzyl, benzoyl, (3-chlorobenzyl),(4-chlorobenzyl), (3-chlorobenzoyl), (4-chlorobenzoyl),(2-fluorobenzyl), (4-fluorobenzyl), (pyridin-2-yl),(pyridin-2-ylmethyl), (pyridin-4-ylmethyl), (pyrimidin-2-ylmethyl),(pyrimidin-4-ylmethyl), (pyrazine-2-carbonyl), cyclopropylmethyl,(cyclopropanecarbonyl), (2,2-difluorocyclopropanecarbonyl),(tetrahydro-2H-pyran-4-yl)methyl, (oxetan-3-yl),(3-methyloxetan-3-yl)methyl, (tetrahydrofuran-3-yl)methyl,(tetrahydrofuran-3-carbonyl), (tetrahydro-2H-pyran-2-yl)methyl,(tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-3-yl)methyl,(1-methyl-1H-imidazol-2-yl)methyl, (4-methylthiazol-5-yl)methyl,(5-methyl-1,3,4-thiadiazol-2-yl)methyl, (1,1-dioxidothietan-3-yl),(1,4-dioxan-2-yl)methyl), (5-oxotetrahydrofuran-2-yl)methyl,(1-methylpyrrolidine-3-carbonyl), (pyrrolidine-3-carbonyl), or(morpholin-2-ylmethyl).

Some embodiments are given by compounds of Formula (I) where R³ and R⁴taken together with the carbons to which they are attached form a sixmember monocyclic ring system, wherein each R⁵, R⁶, R⁷, R⁸, areindependently —H, —F; D is —N(R⁹)—, and R⁹ is(tetrahydrofuran-3-yl)methyl or (tetrahydro-2H-pyran-4-yl)methyl.

Further embodiments are provided by pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically active metabolites ofcompounds of Formula (I).

In certain embodiments, a compound, or a pharmaceutically acceptablesalt thereof, of Formula (I), is selected from the group consisting of:

Example # Compound Name 16-(2-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 26-(3-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 36-(4-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 46-([1,1′-Biphenyl]-4-ylmethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 56-(4-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 66-Benzyl-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;76-([1,1′-Biphenyl]-4-ylmethyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 88-Benzyl-6-(2-chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 98-Benzyl-6-(3-chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 106-(2-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 116-(3-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 126-Benzyl-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;136-(2-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 146-([1,1′-Biphenyl]-4-ylmethyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 156-(4-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 166-(3-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 176,8-Dibenzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 186-([1,1′-Biphenyl]-4-ylmethyl)-8-benzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 196-(2-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 206-(3-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 216-([1,1′-Biphenyl]-4-ylmethyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 228-Benzyl-6-(4-chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 236-(4-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 246-Benzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 256-Benzyl-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 26 6-(4-Chlorobenzyl)-8,9-dimethylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 276-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 28 6-(4-Methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 298-((1,4-Oxazepan-4-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 308-((Dimethylamino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 316-(4-Methoxybenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 326-(4-Methoxybenzyl)-8-((4-methylpiperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 338-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 348-((4-Ethyl-3-oxopiperazin-1-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 356-(4-Methoxybenzyl)-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 368-((2,2-dimethylmorpholino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 378-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 388-(7-oxa-2-azaspiro[3.5]nonan-2-ylmethyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 398-(2-Oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 407-((6-(4-Methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-8-yl)methyl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one; 416-(4-Methoxybenzyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 428-(3,5-Dimethylisoxazol-4-yl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 436-(4-Methoxybenzyl)-9-methyl-8-(pyrrolidin-1-ylmethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 446-(4-Methoxybenzyl)-9-methyl-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 458-((Dimethylamino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 468-((Cyclopropyl(methyl)amino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 478-((4-Hydroxypiperidin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 488-((Benzyl(2-hydroxyethyl)amino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 496-(4-Methoxybenzyl)-9-methyl-8-(piperazin-1-ylmethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 506-(4-Methoxybenzyl)-9-methyl-8-((((3-methyloxetan-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 51 8-((4-Acetylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 526-(4-Methoxybenzyl)-9-methyl-8-(((pyridin-3-ylmethyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 53 6-(4-Methoxybenzyl)-9-methyl-8-((3-oxopiperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 546-(4-Methoxybenzyl)-9-methyl-8-((methyl((tetrahydrofuran-2-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 558-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 568-(Isoindolin-2-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 578-((Cyclopropylamino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 58(S)-6-(4-Methoxybenzyl)-8-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 596-(4-Methoxybenzyl)-9-methyl-8-((methyl((tetrahydrofuran-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 602-(((6-(4-Methoxybenzyl)-9-methyl-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-8-yl)methyl)(methyl)amino)-N,N-dimethylacetamide; 618-((1,4-Oxazepan-4-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 626-(4-Methoxybenzyl)-9-methyl-8-((4-methylpiperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 636-(4-Methoxybenzyl)-9-methyl-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 648-((4-Isopropylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 658-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 668-((4-Ethyl-3-oxopiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 678-(8-Oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 688-((2-Ethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 698-((2,2-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 706-(4-Methoxybenzyl)-9-methyl-8-((2-methylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 71 6-(4-Methoxybenzyl)-9-methyl-8-((3-methylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 728-(((3R,5S)-3,5-Dimethylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 738-((3,4-Dimethylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 746-(4-Methoxybenzyl)-9-methyl-8-((3,3,4-trimethylpiperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 75(S)-8-((Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 768-Bromo-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 778-(Hydroxymethyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 789-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 796-(4-Chlorobenzyl)-8,9-dimethylfuro[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 80 tert-Butyl6-(4-methoxybenzyl)-5-oxo-5,6,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9(8H)-carboxylate; 816-(2-Chlorobenzyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 824-(4-Methoxybenzyl)-2-(morpholinomethyl)pyrazolo[1,5-c]thieno[3,2-e]pyrimidin-5(4H)-one; 836-(4-Chlorobenzyl)-10,10-dimethyl-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 846-Benzyl-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 856-(3-Chlorobenzyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 866-([1,1′-Biphenyl]-4-ylmethyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 876-(4-Chlorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 886-(4-Methylbenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 896-(4-(Trifluoromethyl)benzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 906-(4-Methoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 916-(3,4-Dichlorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 926-(4-Fluorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 936-(4-Chloro-3-fluorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 946-(4-Chloro-2-fluorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 956-(3-Fluoro-4-methoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 966-(4-(Trifluoromethoxy)benzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 976-(4-Ethoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 986-(3,5-Difluoro-4-methoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 996-(4-Chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1006-(3,4-Dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1016-(4-Chlorobenzyl)-9-methyl-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 102 9-Benzyl-6-(4-chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 103 6-(4-Chlorobenzyl)-9-(cyclopropylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 104 2-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-4-(4-methoxybenzyl)pyrazolo[1,5-c]thieno[3,2-e]pyrimidin-5(4H)-one; 1056-(4-Chlorobenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 106 6-(4-Chlorobenzyl)-9-(oxetan-3-yl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 107 6-(4-Chlorobenzyl)-9-(2,2,2-trifluoroethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1086-(4-Methoxybenzyl)-9-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1096-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 110 9-(Cyclopropylmethyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1116-(4-Methoxybenzyl)-9-((3-methyloxetan-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 112 6-(4-Methoxybenzyl)-9-(3-(methylthio)propyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1136-(4-Methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1149-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 115 6-(4-Methoxybenzyl)-9-neopentyl-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 116 6-(4-Methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1176-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1186-(4-Methoxybenzyl)-9-(3-(methylsulfonyl)propyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 119 6-(4-Methoxybenzyl)-9-(pyrimidin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 120 6-(4-Methoxybenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 121 6-(4-Methoxybenzyl)-9-(pyridin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1226-(4-Methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1236-(4-Methoxybenzyl)-9-((4-methylthiazol-5-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1249-(1,1-Dioxidothietan-3-yl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1259-((1,4-Dioxan-2-yl)methyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1266-(4-Methoxybenzyl)-9-((5-oxotetrahydrofuran-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 127 9-(4-Fluorobenzyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 128 9-(2-Fluorobenzyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1296-(4-Chloro-2-fluorobenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1306-(4-Chloro-2-fluorobenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1316-(4-Chloro-2-fluorobenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1326-(4-Chloro-2-fluorobenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1336-(4-Chloro-2-fluorobenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1346-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 13511,11-Difluoro-6-(4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 13611,11-Difluoro-6-(4-methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1376-(2-Fluoro-4-methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1386-(2-Fluoro-4-methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1396-(2-Fluoro-4-methoxybenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1406-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1416-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1426-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1436-(4-Methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 1446-(4-Methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one;145 6-(4-Methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 1466-(4-Methoxybenzyl)-9-(pyridin-2-ylmethyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 147 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one;148 6-(4-Methoxybenzyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1496-(4-Methoxybenzyl)-8-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1506-(4-Methoxybenzyl)-8-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1519-(1,1-Difluoropropan-2-yl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 152 8-(4-Chlorobenzyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 153 8-(4-Chlorobenzyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 154 8-Benzyl-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 155 8-(3-Chlorobenzyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 15611,11-Difluoro-6-(2-fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1576-(4-Chlorobenzyl)-9-(pyrazine-2-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 158 6-(4-Chlorobenzyl)-9-(cyclopropanecarbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 159 9-(Cyclopropanecarbonyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1609-(2,2-Difluorocyclopropanecarbonyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1616-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 162 6-(4-Methoxybenzyl)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1636-(4-Methoxybenzyl)-9-(1-methylpyrrolidine-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1646-(4-Chloro-2-fluorobenzyl)-9-(cyclopropanecarbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1656-(4-Chloro-2-fluorobenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 16611,11-Difluoro-6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1676-(2-Fluoro-4-methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1686-(2-Fluoro-4-methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1699-(Cyclopropanecarbonyl)-6-(2-fluoro-4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 170(R)-6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1716-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1726-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 173(R)-6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 1749-(Cyclopropanecarbonyl)-6-(4-Methoxybenzyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 1758-(Cyclopropanecarbonyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1766-(4-Methoxybenzyl)-8-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 177 8-Benzoyl-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 178 8-(3-Chlorobenzoyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 179 8-(4-Chlorobenzoyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 180 6-(4-Methoxybenzyl)-9-(pyridin-2-yl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 181 6-(4-Methoxybenzyl)-9-(morpholin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 182 6-(4-Methoxybenzyl)-9-(pyrrolidine-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1836-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1846-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,4′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1856-(4-Methoxybenzyl)-9-(piperidin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 186 6-(4-Methoxybenzyl)-8-((4-(pyridin-4-yloxy)piperidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1878-((4-(2-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;188 8-((4-(3-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;189 8-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;190 6-(4-Methoxybenzyl)-9-((3-phenoxypyrrolidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1918-((3-(2-Fluorophenoxy)azetidin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;1926-(4-Methoxybenzyl)-8-((4-morpholinopiperidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1938-((1,1-Difluoro-5-azaspiro[2.4]heptan-5-yl)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;1948-((4-Acetyl-1,4-diazepan-1-yl)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 1958-((1,4-Oxazepan-4-yl)methyl)-6-(2,3-difluoro-4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;196 9-((3-(Hydroxymethyl)-3-isobutylpiperidin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;197 8-(((2,2-Dimethyltetrahydro-2H-pyran-4-yl)(ethyl)amino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;198 9-((Ethyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;199 8-((Ethyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;200 6-(4-Methoxybenzyl)-9-((methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 201 6-(2,3-Difluoro-4-methoxybenzyl)-8-(((2R,6S)-2,6-dimethylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 202 8-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(3-fluoro-4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;203 8-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(2-fluoro-4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;204 6-(4-Methoxybenzyl)-9-((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 205 6-(4-Methoxybenzyl)-8-((methyl(tetrahydro-2H-pyran-4-yl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;206 6-(3-Chloro-4-fluorobenzyl)-8-(((2R,6S)-2,6-dimethylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2078-((1,1-Dioxidothiomorpholino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2086-(3-Fluoro-4-methoxybenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2096-(2-Fluoro-4-methoxybenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2106-(3-Chloro-4-fluorobenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2116-(2,3-Difluoro-4-methoxybenzyl)-8-((methyl((3-methyloxetan-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 212 6-(4-Methoxybenzyl)-8-((((3-methyloxetan-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 213 6-(2,3-Difluoro-4-methoxybenzyl)-8-((3-hydroxyazetidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2146-(2-Fluoro-4-methoxybenzyl)-8-((3-hydroxyazetidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2156-(2,3-Difluoro-4-methoxybenzyl)-8-((dimethylamino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2169-((Diisopropylamino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2176-(4-Methoxybenzyl)-10-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,4′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 218 6-(4-Methoxybenzyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one;219 11,11-Difluoro-9-isobutyl-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 220 11,11-Difluoro-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; and 2216-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.

Isotopically-Labeled Compounds

The invention also includes isotopically-labeled compounds, which areidentical to those recited in Formula I, but for the fact that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of carbon, chlorine, fluorine, hydrogen,iodine, nitrogen, oxygen, phosphorous, sulfur, and technetium, including¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ²H, ³H, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,³¹P, ³²P, ³⁵S, and ^(99m)Tc.

Compounds of the present invention (and derivatives of such compounds,such as pharmaceutically acceptable salts and prodrugs) that contain theaforementioned isotopes or other isotopes of other atoms are within thescope of the invention. Isotopically-labeled compounds of the presentinvention are useful in drug and substrate tissue distribution andtarget occupancy assays. For example, isotopically labeled compounds areparticularly useful in SPECT (single photon emission computedtomography) and in PET (positron emission tomography), as discussedfurther herein.

Derivatives

The present invention also provides derivatives of a chemical entity ofFormula (I), which include, but are not limited to, a salt, solvate,conformer or crystalline form/polymorph. In a specific aspect, thederivative of a chemical entity is a pharmaceutically acceptable salt ofa compound of Formula (I).

Salts

Accordingly, in one embodiment the invention includes pharmaceuticallyacceptable salts of the compounds represented by Formula (I), andmethods using such salts.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, borate, nitrate,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, besylate, mesylateand mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-O-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Solvates

In other embodiments, the invention provides a solvate of a compound ofFormula (I), and the use of such solvates in methods of presentinvention. Certain compounds of Formula (I) or pharmaceuticallyacceptable salts of compounds of Formula (I) may be obtained assolvates. In some embodiments, the solvent is water and the solvates arehydrates.

More particularly, solvates include those formed from the interaction orcomplexes of compounds of the invention with one or more solvents,either in solution or as a solid or crystalline form. Such solventmolecules are those commonly used in the pharmaceutical art, which areknown to be innocuous to the recipient, e.g., water, ethanol, ethyleneglycol, and the like. Other solvents may be used as intermediatesolvates in the preparation of more desirable solvates, such as MeOH,methyl t-butyl ether, EtOAc, (S)-propylene glycol, (R)-propylene glycol,1,4-butyne-diol, and the like. Hydrates include compounds formed by anincorporation of one or more water molecules.

Conformers and Crystalline Forms/Polymorphs

In other embodiments, the invention provides conformer and crystallineforms of a compound of Formula (I), and the use of these derivatives inmethods of present invention. A conformer is a structure that is aconformational isomer. Conformational isomerism is the phenomenon ofmolecules with the same structural formula but different conformations(conformers) of atoms about a rotating bond.

A polymorph is a composition having the same chemical formula, but adifferent solid state or crystal structure. In certain embodiments ofthe invention, compounds of Formula (I) were obtained in crystallineform. In addition, certain crystalline forms of compounds of Formula (I)or pharmaceutically acceptable salts of compounds of Formula (I) may beobtained as co-crystals. In still other embodiments, compounds ofFormula (I) may be obtained in one of several polymorphic forms, as amixture of crystalline forms, as a polymorphic form, or as an amorphousform.

Prodrugs

The invention also relates to prodrugs of the compounds of Formula (I),and the use of such pharmaceutically acceptable prodrugs in methods ofthe present invention, particularly therapeutic methods. Exemplaryprodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines Examples ofesters of the invention include C₁-6alkyl, C₁₋₆cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Fleisher et al., Adv. Drug DeliveryRev. 1996, 19, 115-130.

Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in Robinsonet al., J. Med. Chem. 1996, 39, 10-18. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including ether, amine, andcarboxylic acid functionalities.

Prodrugs may be determined using routine techniques known or availablein the art (e.g., Bundgard (ed.), 1985, Design of prodrugs, Elsevier;Krogsgaard-Larsen et al., (eds.), 1991, Design and Application ofProdrugs, Harwood Academic Publishers).

Metabolites

The present invention also relates to a metabolite of a compound ofFormula (I), as defined herein, and salts thereof. The present inventionfurther relates to the use of such metabolites, and salts thereof, inmethods of present invention, including therapeutic methods.

Metabolites of a compound may be determined using routine techniquesknown or available in the art. For example, isolated metabolites can beenzymatically and synthetically produced (e.g., Bertolini et al., J.Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86,765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; and Bodor, Adv DrugRes. 1984, 13, 224-231).

Compositions

In some embodiments compounds of Formula (I) and pharmaceuticallyacceptable salts thereof are used, alone or in combination with one ormore additional active ingredients, to formulate pharmaceuticalcompositions. A pharmaceutical composition of the invention comprises:(a) an effective amount of at least one active agent in accordance withthe invention; and (b) a pharmaceutically acceptable excipient.

Formulations and Administration

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Osol, ed.), 1980,1553-1593.

Any suitable route of administration may be employed for providing ananimal, especially a human, with an effective dosage of a compound ofthe present invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water, and the like. The particularcarrier, diluent, or excipient used will depend upon the means andpurpose for which the compound of the present invention is beingapplied. Solvents are generally selected based on solvents recognized bypersons skilled in the art as safe (GRAS) to be administered to ananimal. In general, safe solvents are non-toxic aqueous solvents such aswater and other non-toxic solvents that are soluble or miscible inwater. Suitable aqueous solvents include water, ethanol, propyleneglycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixturesthereof. The formulations may also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents and other known additives to provide an elegantpresentation of the drug (i.e., a compound of the present invention orpharmaceutical composition thereof) or aid in the manufacturing of thepharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., acompound of the present invention or stabilized form of the compound(e.g., complex with a cyclodextrin derivative or other knowncomplexation agent)) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound of thepresent invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable and appropriate dosage of thedrug.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways, depending upon the method used toadminister the drug. Generally, an article for distribution includes acontainer having deposited therein the pharmaceutical formulation in anappropriate form. Suitable containers are well-known to those skilled inthe art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The present compounds may be systemically administered, e.g., orally, incombination with a pharmaceutically acceptable vehicle such as an inertdiluent or an assimilable edible carrier. They may be enclosed in hardor soft shell gelatin capsules, may be compressed into tablets, or maybe incorporated directly with the food of the patient's diet. For oraltherapeutic administration, the active compound may be combined with oneor more excipients and used in the form of ingestible tablets, buccaltablets, troches, capsules, elixirs, suspensions, syrups, wafers, andthe like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 60% of the weight of a given unit dosage form. Theamount of active compound in such therapeutically useful compositions issuch that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid, and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are typically prepared by incorporating theactive compound in the required amount in the appropriate solvent with avariety of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, common methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Dosages

Useful dosages of the compounds of Formula (I) can be determined bycomparing their in vitro activity and in vivo activity in animal models.Methods for the extrapolation of effective dosages in mice, and otheranimals, to humans are known to the art. Useful dosages of the compoundsof formula I can be determined by comparing their in vitro activity, andin vivo activity in animal models. Methods for the extrapolation ofeffective dosages in mice, and other animals, to humans are known to theart (e.g., U.S. Pat. No. 4,938,949).

Optimal dosages to be administered in the therapeutic methods of thepresent invention may be determined by those skilled in the art and willdepend on multiple factors, including the particular composition in use,the strength of the preparation, the mode and time of administration,and the advancement of the disease or condition. Additional factors mayinclude characteristics on the subject being treated, such as age,weight, gender, and diet.

In general, however, a suitable dose will be in the range of from about0.01 to about 100 mg/kg, more specifically from about 0.1 to about 100mg/kg, such as 10 to about 75 mg/kg of body weight per day, 3 to about50 mg per kilogram body weight of the recipient per day, 0.5 to 90mg/kg/day, or 1 to 60 mg/kg/day (or any other value or range of valuestherein). The compound is conveniently administered in a unit dosageform; for example, containing about 1 to 1000 mg, particularly about 10to 750 mg, and more particularly, about 50 to 500 mg of activeingredient per unit dosage form.

Preferably, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, and more preferably, about 2 toabout 30 μM. This may be achieved, for example, by the intravenousinjection of a 0.05 to 5% solution of the active ingredient, optionallyin saline, or orally administered as a bolus containing about 1 to 100mg of the active ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01 to 5.0 mg/kg/hr or byintermittent infusions containing about 0.4 to 15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of temporally-distinctadministrations used according to the compositions and methods of thepresent invention.

Effective amounts or doses of the active agents of the present inventionmay be ascertained by routine methods such as modeling, dose escalationstudies or clinical trials, and by taking into consideration routinefactors, e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the agent, the severity and course of the disease,disorder, or condition, the subject's previous or ongoing therapy, thesubject's health status and response to drugs, and the judgment of thetreating physician. Such compositions and preparations should contain atleast 0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be between 2to about 60% of the weight of a given unit dosage form. The amount ofactive compound in such therapeutically useful composition is such thatan effective dosage level will be obtained. An exemplary dose is in therange of from about 0.001 to about 200 mg of active agent per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/daily in single ordivided dosage units (e.g., BID, TID, QID). For a 70-kg human, anillustrative range for a suitable dosage amount is from 1 to 200 mg/day,or about 5 to 50 mg/day.

Methods and Uses Uses of Isotopically-Labeled Compounds

In one aspect, the present invention provides a method of usingisotopically labeled compounds and prodrugs of the present invention in:(i) metabolic studies (preferably with ¹⁴C), reaction kinetic studies(with, for example ²H or ³H); (ii) detection or imaging techniques [suchas positron emission tomography (PET) or single-photon emission computedtomography (SPECT)] including drug or substrate tissue distributionassays; or (iii) in radioactive treatment of patients.

Isotopically labeled compounds and prodrugs of the invention thereof cangenerally be prepared by carrying out the procedures disclosed in theschemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. An ¹⁸F or ¹¹C labeled compound may beparticularly preferred for PET, and an I¹²³ labeled compound may beparticularly preferred for SPECT studies. Further substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements.

Therapeutic Methods Generally

The present invention provides methods of treating a disease, condition,or disorder in an animal by inhibiting PDE1, and more specifically,PDE1B. The methods generally comprise the step of administering atherapeutically effective amount of a compound of the present invention,or a pharmaceutically salt thereof, to a patient in need thereof totreat the disorder or disease. In certain embodiments, the presentinvention provides a use of a compound as described herein in themanufacture of a medicament for treating a disease, condition, ordisorder by inhibiting PDE1, and PDE1B specifically.

PDE1-related indications that can be treated by compounds andcompositions of the present invention include, but are not limited to,nervous system disorders, cardiovascular disorders, metabolic diseases,gastrointestinal and liver diseases, cancer disorders, hematologicaldisorders, pulmonary and vascular diseases, neurological disorders andurological disorders.

PDE1-related indications also encompass diseases (e.g., Parkinson'sdisease or cocaine addiction) that include aberrant or dysregulatedsignaling pathways mediated by PDE1 (e.g., Parkinson's disease orcocaine addiction), and more specifically, PDE1B. Such PDE1-relatedsignaling pathways, preferably in the nervous system, include, but arenot limited to, those involving nitric oxide, natriuretic peptides(e.g., ANP, BNP, CNP), dopamine, noradrenalin, neurotensin,cholecystokinin (CCK), vasoactive intestinal peptide (VIP), serotonin,glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine,adenosine (e.g., A2A receptor), cannabinoids, natriuretic peptides(e.g., ANP, BNP, CNP), and endorphins. Accordingly, compounds of thepresent invention are useful in treating disorders that include anaberrant or dysregulated signaling pathway mediated by PDE1, andspecifically, PDE1B. In a specific aspect, they are useful in treatingdisorders characterized by alterations in dopamine signaling. See, e.g.,Nishi and Snyder, 2010, J Pharmacol. Sci. 114, 6-16.

CNS Disorders

The present invention includes the use of a compound or compositionherein in a method of treating a CNS disorder, comprising administrationof an effective amount of the compound or composition to a patient inneed thereof. More specifically, a compound or composition of thepresent invention can be used in a method to treat a cognitiveimpairment associated with a CNS disorder.

CNS disorders within the scope of the present invention include, but arenot limited to, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, attention deficit disorder (ADD), attention deficithyperactivity disorder (ADHD), neurodegenerative disorders, Tourette'ssyndrome, tic disorders, Lesch-Nyan disease, pain, dystonias, substanceor drug abuse, fetal alcohol syndrome, schizophrenia, schizoaffectivedisorder, depression, affective disorder, manic-depressive disorder,obsessive-compulsive disorder, eating disorder, panic-disorder, anxietydisorder, migraine, myoclonus, premenstrual syndrome, post-traumaticstress syndrome, carcinoid syndrome, stroke, epilepsy, sleep orcircadian rhythm disorder, sexual disorder, stress disorder,hypertension, and nervous system cancers.

In specific embodiments, the CNS disorder is Huntington's disease,schizophrenia, Parkinson's disease, Alzheimer's disease, schizophrenia,mild-cognitive impairment, and ADHD.

In other embodiments, the CNS disorder is substance or drug abuse, orfetal alcohol syndrome.

In one aspect, the compounds of the present invention are useful inimproving neuronal plasticity—an essential property of the brain that isimpaired in numerous CNS disorders. By inhibiting PDE1 activity,compounds of the present invention can enhance levels of Ca²⁺ andcAMP/cGMP, triggering a signaling cascade that ultimately activatestranscription factors, including the cAMP responsive element bindingprotein (CREB). CREB activation can then increase expression of neuronalplasticity-related genes, neurotrophic factors, and neuroprotectivemolecules—which in turn can promote the functional and morphologicalchanges necessary for neuronal plasticity to occur. (See e.g., Tully etal., 2003, Nat. Rev. Drug. Discov. 2, 267-277; Alberini, 2009, Physiol.Rev. 89, 121-145.

More generally, cyclic nucleotide signaling pathways, including thoseinvolving PDE1, are critical regulators of neural function andplasticity, and alterations in these pathways have been implicated invarious disorders of the brain. For example, In Alzheimer's disease,there is evidence that accumulation of amyloid-β protein decreases CREBphosphorylation, resulting in cognitive deficits. Vitolo et al., 2002,Proc. Natl. Acad. Sci. USA. 99, 13217-13221. Indeed, pharmacologicalmethods to increase cAMP levels can restore neuronal plasticity and LTPin Alzheimer's models. Vitolo et al., 2002, Proc. Natl. Acad. Sci. USA.99, 13217-13221. Similarly, intra-cellular signaling of dopamine D1 andvarious serotonin receptors, which signal through cyclic nucleotides, isknown to be defective in various disorders, including depression,schizophrenia and cognitive disorders. In addition, altered cAMP/cGMPlevels are associated with Parkinson's disease, and PDE1B activity isincreased in a Parkinson's model. Sancesario et al., 2004, Eur. J.Neurosci. 20, 989-1000). Moreover, chronic elevation in calcium levels(which has been linked to cell death) is implicated in Alzheimer'sdisease, as well as other neurodegenerative diseases, such asParkinson's and Huntington's. Because calcium signaling can regulatePDE1 function, inhibitors of the present invention are useful intreating such disorders.

Cognitive Impairments

In certain embodiments, compounds and compositions of the presentinvention are used in methods for treating a cognitive impairmentassociated with a neurological disorder. For the purposes of the presentinvention, the term “cognitive impairment” is used interchangeably with“cognitive disorder,” “cognitive dysfunction,” “cognitive deficit,” and“cognitive disability” throughout this application, and all are deemedto cover similar therapeutic indications.

In specific embodiments, the invention provides various methods relyingon the use of compounds and compositions of the present invention totreat a cognitive deficit associated with a CNS disorder, such as acognitive impairment affecting memory formation. In another aspect, acompound or composition of the present invention is administered with acognitive training protocol to treat a cognitive disorder. In a specificaspect, the cognitive deficit is associated with a CNS disorder selectedfrom one or more of the group comprising dementias and neurodegenerativedisorders, progressive CNS diseases, psychiatric disorders,developmental and genetic conditions, age-associated memory impairments,and learning disabilities.

Cognitive disorders can significantly impair social and occupationalfunctioning, adversely impacting the autonomy and quality of life of theaffected individual. An estimated four to five million Americans (about2% of all ages and 15% of those older than 65) have some form and degreeof cognitive impairment. Abrams et al., Merck Manual of Geriatrics,Whitehouse Station (NJ), Medical Services (1995).

Cognitive disorders reflect problems in cognition, i.e., the generalprocesses by which knowledge is acquired, retained and used.Accordingly, cognitive disorders can encompass impairments in cognitivefunctions such as concentration, perception, attention, informationprocessing, learning, memory, and/or language. Cognitive disorders canalso encompass impairments in psychomotor learning, which includephysical skills, such as movement and coordination; disruptions in finemotor skills, such as the ability to use precision instruments or tools;and deficits in gross motor skills, such as those elicited in dance,musical, or athletic performance.

Cognitive disorders can also encompass impairments in executivefunctions, which include abilities underlying the planning and executionof goal-oriented behaviors. Such abilities include flexibility, i.e.,the capacity for quickly switching to the appropriate mental mode;anticipation and prediction based on pattern recognition; reasoning andproblem-solving; decision making; working memory, i.e., the capacity tohold and manipulate internally (or externally) derived information inreal time; emotional self-regulation, including the ability to recognizeand manage one's emotions for good performance; sequencing, such as theability to dissect complex actions into manageable units and prioritizethem in the right order; and self-inhibition, i.e., the ability towithstand distraction and internal urges.

Cognitive disorders commonly occur in association with CNS disorders(also referred to as CNS conditions or CNS diseases). Such CNS disordersinclude, but are not limited to, the following categories (which are notmutually exclusive):

-   -   (1) dementias, such as those associated with Alzheimer's        disease, Parkinson's disease; Huntington's disease, Pick's        disease, Creutzfeldt-Jakob, ALS, AIDS Dementia, and other        neurodegenerative disorders; as well as cognitive disabilities        associated with progressive diseases involving the nervous        system, such as multiple sclerosis.    -   (2) psychiatric disorders, which include affective disorders        (mood disorders), such as depression and bipolar disorder;        psychotic disorders, such as schizophrenia and delusional        disorder; and neurotic and anxiety disorders, such as phobias,        panic disorders, obsessive-compulsive disorder, generalized        anxiety disorder, eating disorders, and posttraumatic stress        disorder;    -   (3) developmental and genetic conditions affecting cognitive        function, such as autism spectrum disorders; fetal alcohol        spectrum disorders (FASD); Rubinstein-Taybi syndrome, down        syndrome, and other forms of mental retardation; and progressive        disorders involving the nervous system, such as multiple        sclerosis;    -   (4) trauma-dependent losses of cognitive functions, such as        impairments in memory, language, or motor skills resulting from        brain trauma; head injury; cerebrovascular disorders, such as        stroke, ischemia, hypoxia, and viral infection (e.g.,        encephalitis); excitotoxicity; seizures; and alcohol abuse;    -   (5) age-associated memory impairments, including those affecting        patients in early stages of cognitive decline, as in Mild        Cognitive Impairment (MCI); and    -   (6) learning disabilities, such as perceptual handicaps,        dyslexia, and attention deficit disorders.

In some cases, cognitive impairments can be a direct result of a CNSdisorder. For example, impairments in speech and language may be adirect result of a stroke or head-injury that damages the brain regionscontrolling speech and language, as in aphasia.

In other cases, cognitive impairments may be associated with a complexdevelopmental syndrome, CNS disorder, or genetic syndrome. For example,such impairments include cognitive deficits associated withschizophrenia or Parkinson's disease, or deficits in executive controlthat accompany autism or mental retardation.

In still other cases, such impairments can result from progressivediseases that impact CNS function, such as multiple sclerosis (MS).About one-half of MS patients will experience problems with cognitivefunction, such as slowed thinking, decreased concentration, and impairedmemory. Such problems typically occur later in the course of MS,although in some cases they occur much earlier—if not at the onset ofdisease.

Augmented Cognitive Training

In some embodiments, the compounds and compositions of the instantinvention are administered in conjunction with cognitive training toimprove the efficiency of such training. The phrase “in conjunction”means that a compound or composition of the present invention enhancesCREB pathway function during cognitive training. As used herein, theterm “cognitive training” is interchangeable with “training protocol,”“training,” and “cognitive training protocol.”

Training Protocols

Cognitive training protocols and the underlying principles are wellknown in the art. See, e.g., U.S. Pat. No. 7,868,015 (and referencescited therein); Klingberg et al., 2005, J. Am. Acad. Child. Adolesc.Psychiatry 44, 177-186; Belleville et al., 2006, Dement. Geriatr. Cogn.Disord. 22, 486-499; Jaeggi et al., 2008, Proc. Natl. Acad. Sci. USA105, 6829-6833; Lustig et al., 2009, Neuropsychol. Rev. 19, 504-522;Park and Reuter-Lorenz, 2009, Ann. Rev. Psych. 60, 173-196; Chein etal., 2010, Psychon. Bull. Rev. 17, 193-199; Klingberg, 2010, TrendsCogn. Sci. 14, 317-324; Owen et al., 2010, Nature 465, 775-778; Jaeggiet al., 2011, Proc. Natl. Acad. Sci. USA 108, 10081-10086.

Cognitive training protocols are directed to numerous cognitivedimensions, including memory, concentration and attention, perception,learning, planning, sequencing, and judgment. One or more protocols (ormodules) underling a cognitive training program can be provided to asubject.

In some embodiments, the protocols can be used to treat, orrehabilitate, cognitive impairments in afflicted subjects. Suchprotocols may be restorative or remedial, intended to reestablish priorskills and cognitive functions, or they may be focused on delaying orslowing cognitive decline due to neurological disease. Other protocolsmay be compensatory, providing a means to adapt to a cognitive deficitby enhancing function of related and uninvolved cognitive domains. Inother embodiments, the protocols can be used to improve particularskills or cognitive functions in otherwise healthy individuals. Forexample, a cognitive training program might include modules focused ondelaying or preventing cognitive decline that normally accompaniesaging; here the program is designed to maintain or improve cognitivehealth.

In general, a cognitive training protocol (or module) comprises a set ofdistinct exercises that can be process-specific or skill-based:

Process-specific training focuses on improving a particular cognitivedomain such as attention, memory, language, or executive functions. Herethe goal of cognitive training is to obtain a general improvement thattransfers from the trained activities to untrained activities associatedwith the same cognitive function or domain. For example, an auditorycognitive training protocol can be used to treat a student with impairedauditory attention. At the end of training, the student should show ageneralized improvement in auditory attention, manifested by anincreased ability to attend to and concentrate on verbal informationpresented in class—and therefore to remember to write down and completehomework assignments. Similarly, a cognitive training protocol may bedirected to impaired executive function in an autistic subject,preventing the subject from carrying out instructions to complete anactivity, such as making a meal, cleaning one's room, or preparing forschool in the morning. Cognitive training allows the subject to focushis attention and concentration and as a result, complete the sequenceof tasks required for such activities.

Skill-based cognitive training is aimed at improving performance of aparticular activity or ability. Here the goal of cognitive training isto obtain a general improvement in the skill or ability. For example, atraining protocol may focus on learning a new language, performing amusical instrument, or improving memory. The different exercises withinsuch a protocol will focus on core components underlying skill. Modulesfor increasing memory, for example, may include tasks directed to therecognition and use of fact, and the acquisition and comprehension ofexplicit knowledge rules.

Some cognitive rehabilitation programs may rely on a single strategy(such as computer-assisted cognitive training) targeting either anisolated cognitive function or multiple functions concurrently. Forexample, the CogState testing method comprises a customizable range ofcomputerized cognitive tasks able to measure baseline and change incognitive domains underlying attention, memory, executive function, aswell as language and social-emotional cognition. See, e.g., Yoshida etal., 2011, PloS ONE 6, e20469; Frederickson et al., 2010,Neuroepidemiology 34, 65-75. Other cognitive rehabilitation programs mayuse an integrated or interdisciplinary approach. Cognitive trainingprograms may involve computer games, handheld game devices, interactiveexercises, and may employ feedback and adaptive models.

Augmenting Agents

Cognitive training generally requires multiple training sessions toattain the desired benefits. This can be costly and time-consuming,deterring subject compliance and the realization of real world benefitsthat endure over time.

The efficiency of cognitive training can be improved by administeringcertain agents (known as augmenting agents) in conjunction withcognitive training. Such augmenting agents have the ability to enhanceCREB pathway function. More particularly, this method (known asaugmented cognitive training or ACT) can decrease the number of trainingsessions required to improve performance of a cognitive function,relative to the improvement observed by cognitive training alone. See,e.g., U.S. Pat. No. 7,868,015; U.S. Pat. No. 7,947,731; U.S.2008/0051437.

In a particular embodiment, the method comprises the steps of: (a)providing cognitive training to a subject in need of treatment of acognitive deficit under conditions sufficient to produce an improvementin performance by said animal of a cognitive function whose impairmentis associated with said cognitive deficit; (b) administering a compoundor composition of the present invention to the animal in conjunctionwith said cognitive training; repeating steps (a) and (b) one or moretimes; and (d) reducing the number of training sessions sufficient toproduce the improvement in performance, relative to the improvement inperformance produced by cognitive training alone.

More generally, compounds and compositions of the present invention canbe used in conjunction with any psychotherapeutic approach that isintended to modulate cognitive function in the brain, thereby enhancingthe efficacy of the such therapy by reducing the number of sessions—andhence time—necessary to attain benefits.

In a specific aspect, the cognitive deficit treated by these methods isor includes memory impairment, and more particularly, a defect inlong-term memory. Long-term memory (LTM) generally comprises two mainbiological properties. First, formation of long-term memory requiressynthesis of new proteins. Second, it involves cAMP-responsivetranscription and is mediated through the cAMP-response element bindingprotein (CREB) family transcription factors. Accordingly, in someembodiments, compounds of the present invention are useful in enhancingmemory formation in an animal, and more particularly,transcription-dependent memory.

Behavioral Assays

Numerous behavioral assays are available to assess the ability of acandidate compound to enhance memory formation, including the contextualconditioning, temporal conditioning, and object recognition assays. (SeeBiological Examples) Other, non-limiting examples of appropriatetraining protocols to assess memory include those that incorporate orrelate to multiple training sessions, spaced training sessions,contextual fear training with single or multiple trials, trace fearconditioning with single or multiple trials, contextual memorygenerally, temporal memory, spatial memory, episodic memory, passiveavoidance memory, active avoidance memory, food preference memory,conditioned taste avoidance, and social recognition memory.

The training protocols can also be used in accordance with the presentinvention as will be understood by those of ordinary skill in the art.These training protocols can be directed towards the evaluation of,without limitation, hippocampus-, cortex, and/or amygdale-dependentmemory formation or cognitive performance.

Cardiovascular Disorders

PDE1 enzymes and cyclic nucleotides are emerging as key mediators ofpathological processes that underlie many vascular disorders, includinghypertension and myocardial infarction. For example, PDE1 appears toplay a role in regulating cardiomyocyte hypertrophy via a mechanisminvolving cross-talk between Ca2+ and cyclic nucleotide signaling. See,e.g., Miller et al., 2011, Basic Res. Cardiol. 106, 1023-1039; Miller etal, 2009, Circ. Res. 105, 956-964. Moreover, PDE1 enzymes constitute themajority of cAMP- and cGMP-hydrolytic activity in human myocardium,implicating them in regulating signaling pathways involved in heartfailure

Accordingly, the present invention includes the use of a compound orcomposition herein in a method of treating a cardiovascular disorder,comprising administration of an effective amount of the compound orcomposition to a patient in need thereof.

Cardiovascular diseases within the scope of the present inventionencompass, but are not limited to, angina pectoris, coronary arterydisease, hypertension, congestive heart failure, myocardial infarction,ischemic diseases of the heart, atrial and ventricular arrhythmias,hypertensive vascular diseases, peripheral vascular diseases, andatherosclerosis.

In some embodiments, methods of treating a cardiovascular disorder inaccord with the present invention comprise increasing cGMPconcentration, cAMP concentration, or both, in any part of the heartmuscle of a subject, the method comprising administering to the subjecta compound or composition described herein.

In other embodiments, compounds of the present invention may be usefulin lowering the heart rate or blood pressure in an animal.

Renal Disorders

PDE1 inhibitors are emerging therapeutic agents for progressive renaldisease. See, e.g., Cheng et al., 2007, Soc. Exp. Biol. Med. 232, 38-51.Consistent with these findings, recent studies indicate that cAMP andcGMP regulate a variety of signaling pathways involved in thedevelopment and progression of renal disease, including pathways thatmodulate mitogenesis, inflammation, and extracellular matrix synthesis.See e.g., Wang et al., 2010, Kidney Int. 77. 129-140.

Accordingly, the present invention provides compound or compositions inmethods for treating a renal disorder, comprising administering aneffective amount of the compound or composition to a patient in needthereof. In a particular aspect, the renal disorder is selected from oneor more of the group comprising renal artery stenosis, pyelonephritis,glomerulonephritis, kidney tumors, polycystic kidney disease, injury tothe kidney, and damage resulting from radiation of the kidney.

Hematological Disorders

PDE1B is highly expressed in the hematological system, includingleukocytes (peripheral blood), bone marrow stromal cells, bone marrowCD33+ cells, cord blood CD34+ cells, neutrophils cord blood, neutrophilsperipheral blood, spleen, spleen liver cirrhosis. Accordingly, thepresent invention includes methods to treat a hematological disorder,comprising administering a compound or composition herein to a patientin need thereof. Hematological diseases within the scope of the presentinvention comprises disorders of the blood and all its constituents,including, but not limited to anemias, myeloproliferative disorders,hemorrhagic disorders, leukopenia, eosinophilic disorders, leukemias,lymphomas, plasma cell dyscrasias, and disorders of the spleen.

Gastrointestinal and Liver Diseases

PDE1B shows differential expression between diseased (e.g., cancerous)and healthy stomach tissue, diseased (e.g., cancerous) versus healthyileum tissue, diseased (cirrhotic) versus and healthy liver.Accordingly, the present invention includes methods to treat agastrointestinal disorder, comprising administering a compound orcomposition herein to a patient in need thereof. Gastrointestinaldiseases within the scope of the present invention comprise, but are notlimited to, disorders of the esophagus, stomach, duodenum, pancreas,bowel, and liver.

Cancer Disorders

PDE1B shows high expression in numerous cancer tissues, including tumorsof the stomach, ileum, ovary, breast, and kidney, as well asdifferential expression between cancerous and healthy stomach, ileum,lung, ovary, breast, and kidney. Accordingly, the present inventionincludes methods to treat a cancer disorder, comprising administering acompound or composition herein to a patient in need thereof. Cancerdisorders within the scope of the present invention comprise, but arenot limited to, neoplasms, dysplasias, hyperplasias, and neoplasms,including cancers of the stomach, ileum, ovary, breast, and kidney.

Neurodegenerative Disorders

The present invention provides a method for treating the effects ofinjuries or diseases that result in neuronal degeneration or a methodfor promoting neurogenesis or neurite outgrowth These methods involveadministering to a patient in need thereof an effective amount of acompound or composition of the present invention. It has been found thatthe PDE1 inhibitors of the present invention promote neurite outgrowthand neurogenesis.

Alternatively, at least one compound of the present invention is used totreat stem cells or neuronal progenitor cells prior to the cells beingadministered to the patient by implantation at the site of neuronaldegeneration. In some embodiments, methods described herein involvemodulating neurogenesis or neurite outgrowth ex vivo with a compoundsuch that a composition containing neural stem cells, neural progenitorcells and/or differentiated neural cells can be subsequentlyadministered to an individual to treat a disease or condition. In someembodiments, the method of treatment comprises the steps of contacting aneural stem cell or neural progenitor cell with one or more compounds ofthe invention to modulate neurite outgrowth and transplanting the cellsinto a patient in need or treatment. Methods of transplanting stem andprogenitor cells are known in the art. In some embodiments, methodsdescribed herein allow treatment of diseases or conditions by directlyreplacing or replenishing damaged or dysfunctional neurons.

The method of the present invention which promotes neurogenesis isinvolved in cell renewal in the central nervous system (CNS) andincludes all types of CNS cells.

In one embodiment, methods of the present invention are used to treatprimary nervous system injury, e.g. closed head injuries and blunttrauma, such as those caused by participation in dangerous sports,penetrating trauma, such as gunshot wounds, hemorrhagic stroke, ischemicstroke, glaucoma, cerebral ischemia, or damages caused by surgery suchas tumor excision or may even promote nerve regeneration in order toenhance or accelerate the healing of such injuries or ofneurodegenerative diseases such as those discussed below. In addition,the method may be used to treat a disease or disorder resulting in adegenerative process.

In another embodiment, methods of the present invention are used toinhibit secondary degeneration which may otherwise follow primarynervous system injury.

The compounds of the invention may be used to treat various diseases ordisorders of the central or peripheral nervous system, includingdiabetic neuropathy, amyotrophic lateral sclerosis (ALS). Peripheralnerve injuries and peripheral or localized neuropathies including, butnot limited to, porphyria, acute sensory neuropathy, chronic ataxicneuropathy, complications of various drugs and toxins, amyloidpolyneuropathies, adrenomyeloneuropathy, giant axonal neuropathy may betreated by this method.

In addition the compounds can be used for post-operative treatments suchas for tumor removal from CNS and other forms of surgery on the CNS. Thecompounds can also be used for treatment of spinal cord trauma.

EXAMPLES

The present disclosure will be further illustrated by the followingnon-limiting Examples. These Examples are understood to be exemplaryonly, and they are not to be construed as limiting the scope of theinvention herein, and as defined by the appended claims.

Preparative Examples

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

Synthetic Schemes

One skilled in the art will recognize that, to obtain the variouscompounds herein, starting materials may be suitably selected so thatthe ultimately desired substituents will be carried through the reactionscheme with or without protection as appropriate to yield the desiredproduct. Alternatively, it may be necessary or desirable to employ, inthe place of the ultimately desired substituent, a suitable group thatmay be carried through the reaction scheme and replaced as appropriatewith the desired substituent. Unless otherwise specified, the variablesare as defined above in reference to Formula (I). Reactions may beperformed between −78° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

According to Scheme 1, Method A, amino-cyanothiophenes of formula (IV)are commercially available or are prepared from commercially availableor synthetically accessible ketones and aldehydes of formula (III),using methods known to one skilled in the art. For example, heatingketones and aldehydes of formula (III), where R³ and R⁴ areindependently —H, —C₁₋₆alkyl, and benzyl, in the presence of elementalsulfur and an appropriate active methylene, such as malonitrile and thelike, with an organic base such as imidazole, TEA, diethylamine,piperidine, and the like, in a solvent such as DMF, EtOH, dioxane, THF,and the like, at temperatures ranging from room temperature to 80° C.,for a period of 12 to 24 h, provides amino-cyanothiophenes of formula(IV). In some cases, regioisomeric thiophenes may form.Amino-cyanothiophenes of formula (IV) are alkoxyformylated with areagent such as chloroformates of formula R¹⁵OC(O)Cl, where R¹⁵ is —CH₃or —CH₂CH₃, and the like, a base such as pyridine, disodium carbonateand the like, in a solvent such as DCM, DCE, or a mixture thereof, atemperatures ranging from 0° C. to room temperature, for a period of 12to 24 h, provides carbonates of formula (V). Compounds of formula (V)are optionally brominated, employing a brominating agent, such as, butnot limited to, Br₂, in the presence of sodium acetate, in a solventsuch as, but not limited to, acetic acid, at temperatures ranging from23° C. to 60° C., preferably 60° C. for a period of 24 h, to providecarbonates of formula (V) where R³ is —Br. Carbonates of formula (V),when heated with formylhydrazine, a base such as tri-n-propylamine, in asolvent such as 2-methoxyethanol, at temperatures ranging from roomtemperature to 130° C., for a period of 12 to 30 h, afford thetriazolopyrimidinone compounds of formula (VI).

Furan-fused derivatives are prepared in a manner similar to theirthiophene counterparts. Commercially available or syntheticallyaccessible aminofurancaronitriles of formula (IV), where Y is —O—, arealkoxyformylated and treated with formyl hydrazide to givetriazolopyrimidinone intermediates as described above.

According to Scheme 1, Method B, triazolopyrimidinone intermediateswhere R³ and R⁴ come together to form a ring, where D is —N(R⁹)—, areprepared in three steps from commercially available or syntheticallyaccessible compounds of formula (VIII), where R⁹ is a suitableprotecting group PG, such as tert-butyloxycarbonyl, benzyl,benzyloxycarbonyl, and the like, employing methods previously describedin Route A. Compounds of formula (IX), where D is a bond, —O—, or—N(R⁹)— are alternately prepared via a three-component Gewald reaction,for example, by reacting an appropriately substituted carbonyl compound,malononitrile, S₈ (elemental sulfur), a catalyst such as L-proline, in asolvent such as EtOH, DMSO, DMF, and the like, at temperatures rangingfrom room temperature to 110° C., for a period of 2 to 30 h. Subsequentalkoxyformylation and treated with formyl hydrazide to givetriazolopyrimidinone intermediates (X) as described above.

According to Scheme 1, Method C,2-amino-4-oxo-4,5-dihydrothiophene-3-carbonitrile (XI) is commerciallyavailable or synthetically accessible from the reaction of malonitrile,2-chloroacetyl chloride, a base such as pyridine, and the like, in asolvent such as DCM, at temperatures ranging from 0° C. to roomtemperature, for a period of 8 to 24 h.2-Amino-4-oxo-4,5-dihydrothiophene-3-carbonitrile (XI) isalkoxyformylated according to methods previously described.4-Cyano-5-((methoxycarbonyl)amino)thiophen-3-yltrifluoromethanesulfonate (XII) is prepared by reaction of methyl(3-cyano-4-oxo-4,5-dihydrothiophen-2-yl)carbamate, withtrifluoromethanesulfonic anhydride, a base such as TEA and the like, ina solvent such as DCM, at temperatures ranging from 0° C. to roomtemperature, for a period of 12 to 24 h.5-Oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-9-yltrifluoromethanesulfonate (XIII) is treated with formyl hydrazide togive triazolopyrimidinone intermediates as described above.

According to Scheme 1, Method D, commercially available4-bromo-5-nitrothiophene-2-carbaldehyde (XIV) is coupled with(1H-pyrazol-5-yl)boronic acid under Suzuki reaction conditions known toone skilled in the art, for example, reaction with(1H-pyrazol-5-yl)boronic acid, in a solvent such as ethyleneglycoldiemethyl ether, a base such as TEA, with or without the addition ofH₂O, a palladium catalyst such asbis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM,and the like, at temperatures ranging from 60 to 90° C., for a period ofabout 3 to 6 h, provides5-nitro-4-(1H-pyrazol-3-yl)thiophene-2-carbaldehyde (XV). Reduction ofthe nitro moiety, under conditions known to one skilled in the art, suchas sodium hydrosulfite in water, in a solvent such as EtOH, and thelike, at room temperature, provides5-amino-4-(1H-pyrazol-3-yl)thiophene-2-carbaldehyde.5-Oxo-4,5-dihydropyrazolo[1,5-c]thieno[3,2-e]pyrimidine-2-carbaldehyde(XVI) is prepared from the reaction of5-amino-4-(1H-pyrazol-5-yl)thiophene-2-carbaldehyde,bis(trichloromethyl) carbonate, a solvent such as toluene, THF, or amixture thereof, at temperatures ranging from 80 to 110° C., for aperiod of about 3 to 6 h, in a sealed tube.

According to Scheme 2, Compounds of Formula (I) are prepared fromtriazolopyrimidinone compounds of formula (VI), (XI), (XIII) or (XVI),by reaction with a suitable electrophile of formula (VII), where LG is aleaving group such as —Cl, —Br, —O—SO₂CH₃, and the like, a base such asK₂CO₃, NaH, and the like, in a suitable solvent such as DMF, attemperatures ranging from room temperature to 60° C., for a period of 12to 30 h.

According to Scheme 3, compounds of Formula (I), where R³ or R⁴ is —Bror —OTf, are converted to thienocarbaldehydes of formula (XX), in twosteps. Reaction of compounds of Formula (I), where R³ or R⁴ is —Br or—OTf, with a vinylorganometallic reagent such as potassiumtrifluoro(vinyl)borate, a palladium catalyst such as PdCl₂(dppf)-DCM,complex with DCM, a base such as TEA, in a solvent such as butan-1-ol,at temperatures ranging from 60 to 100° C., for a period of 12 to 24 h,provides the corresponding vinylthiophene. Alternately, thiophenecompounds of Formula (I) may be converted to vinylthiophenes, underStille conditions, by reaction with a vinylorganometallic reagent suchas vinyltributylstannane. Other examples of vinylorganometallic reagentsthat may be employed are organozinc and organomagnesium reagents.Vinylthiophenes, are subsequently oxidized to aldehydes of formula (XX)using a suitable method, for example, osmium(VIII)oxide, sodiumperiodate in water-THF, at temperatures ranging from 40 to 60° C., for aperiod of 2 to 4 h. Alternatively, ozonolysis may be employed to provide2-thienocarbaldehydes of formula (XX). Thienocarbaldehydes of formula(XX), are also prepared by reaction of compounds of Formula (I), where Xis N, R³ is H and R⁴ is —C₁₋₆alkyl, under Vilsmeier-Haak reactionconditions, with phosphorous oxychloride and dimethylformamide, with orwithout a solvent such as DCM, 1,4-dioxane, THF and the like, attemperatures ranging from room temperature to 80° C., for a period of0.5 to 6 h. Thienocarbaldehydes of formula (XX) and (XVIII), where R³ orR⁴ is —CHO, are a reacted under reductive amination conditions, forexample, by reacting with commercially available or syntheticallyaccessible alkyl, aryl, carbocycloalkyl, heteroaryl, or heterocycloalkylamines of formula —NHR¹²R¹³, in the presence of a reducing agent such assodium cyanoborohydride, sodium triacetoxyborohydride, and the like,with or without a catalytic amount of acetic acid, in a solvent such asDMF, methanol, 1,4-dioxane, THF, DCM, or a mixture thereof, attemperatures ranging from room temperature to the reflux temperature ofthe solvent, for a period of 3 to 24 h, to afford compounds of Formula(I) where X is —N— or —CH—, and R³ or R⁴ is —CH₂NR¹²R¹³ and NR¹²R¹³ aretaken together with the nitrogen to which they are attached form anoptionally substituted heterocycloalkyl ring.

Thienocarbaldehydes of formula (XX) are reduced, with a reducing agentsuch as sodium borohydride, in a solvent such as methanol, and the like,at temperatures ranging from room temperature to 60° C., for a period ofabout 1 to 4 h, to provide alcohol compounds of Formula (I), where R³ isCH₂OH, and R⁴ is —C₁₋₆alkyl.

Compounds of Formula (I) are further elaborated as described below.

Bromothiophene compounds of Formula (I), where R³ is —Br, and R⁴ is H,are converted to compounds of Formula (I), where R³ is an optionallysubstituted heteroaryl, under Stille conditions. For example, reactionwith a heteroaryltributylstannane reagent such as, but not limited to,1-methyl-5-(tributylstannyl)-3-(trifluoromethyl)-1H-pyrazole, in asolvent such as toluene, and the like, at temperatures ranging from 80to 110° C., for a period of 8 to 20 h, provides compounds of Formula(I), where R³ is an optionally substituted heteroaryl.

Deprotection of compounds of Formula (I), where R⁹ istert-butyloxycarbonyl, benzyl, or benzyloxycarbonyl, is accomplishedusing methods known to one skilled in the art. For example, removal ofthe tert-butylcarbamate (BOC) in compounds of Formula (I), where R³ andR⁴ come together to form a ring, where D is —N(R⁹)—, and R⁹ istert-butyloxycarbonyl, employing methods known to one skilled in theart, such as, HCl, TFA, or p-toluenesulfonic acid, in a solvent such asCH₃OH, dioxane, or DCM, affords compounds of Formula (I) where R⁹ is H.

Compounds of Formula (I), where R³ and R⁴ come together to form a ring,where D is —N(R⁹)—, and R⁹ is H, are alkylated with electrophiles, suchas an appropriately substituted alkyl, aryl, carbocycloalkyl,heteroaryl, or heterocycloalkyl group substituted with a leaving groupselected from —Cl, —Br, —O—SO₂CH₃, and the like, a base such as K₂CO₃,NaH, and the like, in a suitable solvent such as DMF, at temperaturesranging from room temperature to 60° C., for a period of 12 to 30 h.

Alternatively, compounds of Formula (I), where R³ and R⁴ come togetherto form a ring, where D is —N(R⁹)—, and is H, are a reacted underreductive amination conditions, for example, by reacting withcommercially available or synthetically accessible alkyl, aryl,carbocycloalkyl, heteroaryl, or heterocycloalkyl aldehyde or ketones, inthe presence of a reducing agent such as sodium cyanoborohydride, sodiumtriacetoxyborohydride, and the like, in a solvent such as THF, DCM, or amixture thereof, at temperatures ranging from room temperature to thereflux temperature of the solvent, for a period of 3 to 24 h.

Compounds of Formula (I), where R³ and R⁴ come together to form a ring,where D is —N(R⁹)—, and R⁹ is H, are additionally reacted withoptionally substituted alkyl, aryl, or heteroaryl carboxylic acids, acidchlorides or sulfonyl chlorides, under conditions known to one skilledin the art, to afford compounds of Formula (I), where R⁹ is anoptionally substituted —CO₂C₁₋₆alkyl, —SO₂(C₁₋₆alkyl), —CO(aryl),—CO(heteroaryl), —CO(heterocycloalkyl) or —CO(C₃₋₆cycloalkyl).

EXAMPLES Chemistry

In obtaining the compounds described in the examples below, and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under nitrogen atmosphere. Where solutions were“dried”, they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure.

Reactions under microwave irradiation conditions were carried out in aCEM Discover-SP with Activent microwave reaction apparatus, model number909150, or Biotage Initiator, model number 355302.

Normal-phase flash column chromatography (FCC) was performed on silicagel (SiO₂) using packed or prepackaged cartridges, eluting with theindicated solvents.

LC/MS were obtained on a Waters 2695 Separations Unit, 2487 DualAbsorbance Detector, Micromass ZQ fitted with ESI Probe, or a WatersAcquity™ Ultra performance LC (UPLC) with PDA eλ and SQ detectors.

Preparative HPLC was performed on a Shimadzu SIL-10AP system using aWaters SunFire OBD 30 mm×100 mm×2.5 μm (particle size) C¹⁸ column with a15 minute gradient of 10-100% acetonitrile in water and 0.05%trifluoroacetic acid added as a modifier to both phases. Elutionprofiles were monitored by UV at 254 and 220 nm.

Nuclear magnetic resonance (NMR) spectra were obtained in a Varian 400MHz or Bruker 400 MHz NMR. Samples were analyzed in either deuteratedacetone ((CD₃)₂CO)), chloroform (CDCl₃), methanol-d₄ (CD₃OD), ordimethyl sulfoxide-d₆ (DMSO-d₆). For CDCl₃ samples, the residual centralresonance peak at 7.26 for ¹H was used for chemical shift assignment for¹H NMR spectra. For CD₃OD the residual central resonance peak at 3.31for ¹H was used for chemical shift assignment and for DMSO-d₆ theresidual central resonance peak at 2.50 ppm for ¹H was used for chemicalshift assignment. The format of the ¹H NMR data below is: chemical shiftin ppm downfield the tetramethylsilane reference (multiplicity, couplingconstant J in Hz, integration).

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoftCorp., Cambridge, Mass.) or ChemAxon.

Example 16-(2-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

Step A: Methyl 3-cyanothiophen-2-ylcarbamate. Methyl chloroformate (7.61g, 80.5 mmol) was added drop-wise to a stirred of2-amino-3-cyanothiophene (10 g, 80.5 mmol) and pyridine (19.1 g, 242mmol) in DCM (250 mL) at 0° C. After addition, the mixture was warmed toroom temperature and stirred overnight. The reaction was treated withwater (50 mL) and extracted with DCM (3×150 mL). The combined organicphase was washed with 1 N HCl (2×150 mL), saturated aqueous sodiumbicarbonate (100 mL), brine (100 mL), and dried over sodium sulfate. Theorganic layers were filtered and concentrated under reduced pressure toafford the crude product, which was triturated with a solution of methyltert-butyl ether and petroleum ether (1:1, 50 mL) to afford the titlecompound, (11 g, 75%) as a pale white solid. ¹H NMR (400 MHz, CDCl₃) δ3.90 (s, 3H), 6.63-6.65 (d, 1H), 6.94-6.96 (d, 1H), 7.94 (s, 1H).

Step B: Thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.Formylhydrazine (2.08 g, 34.6 mmol) and tri-n-propylamine (3 mL) wasadded to a suspension of methyl 3-cyanothiophen-2-ylcarbamate (6 g, 32.9mmol) in 2-methoxyethanol (70 mL) at room temperature. The mixture washeated at reflux overnight under nitrogen. The mixture was concentratedunder vacuum to give a crude product, which was purified by preparativeHPLC to afford the title compound (1.8 g, 26%) as a solid. ¹H NMR (400MHz, DMSO-d₆) δ 7.28-7.30 (d, 1H), 7.39-7.41 (d, 1H), 8.34 (s, 1H).

Step C:6-(2-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.Potassium carbonate (302 mg, 2.19 mmol) was added to a suspension ofthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (140 mg, 0.73mmol) in DMF (3 mL) and the mixture was stirred for 10 minutes.1-Bromomethyl-2-chloro-benzene (180 mg, 0.87 mmol) was added and themixture was stirred overnight at 40° C. The mixture was concentrated invacuum and the residue was diluted with water (10 mL) and extracted withDCM (3×30 mL). The combined organic extracts were washed with brine (30mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was triturated with a solution of methyltert-butyl ether-DCM (20:1) to afford the title compound (63 mg, 22%) asa white powder. ¹H NMR (400 MHz, CDCl₃) δ 5.64 (s, 2H), 7.08 (d, 1H),7.13 (d, 1H), 7.20 (t, 1H), 7.25 (t, 1H), 7.48 (d, 1H), 7.61 (d, 1H),8.35 (s, 1H). [M+H]=317.0.

Examples 2 thru 28 were made in a manner analogous to Example 1, withthe appropriate starting material and reagent substitutions.

Example 26-(3-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 5.64 (s, 2H), 7.16 (d, 1H), 7.35-7.25 (m, 3H),7.48 (s, 1H), 7.62 (d, 1H), 8.33 (s, 1H). [M+H]=317.0.

Example 36-(4-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.67 (s, 3H), 5.40 (s, 2H), 6.74 (s, 1H), 7.33(d, 2H), 7.43 (d, 2H), 8.33 (s, 1H). [M+H]=331.0.

Example 46-([1,1′-Biphenyl]-4-ylmethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 5.49 (s, 2H), 7.14 (d, 1H), 7.35 (m, 1H), 7.42(t, 2H), 7.57 (m, 7H), 8.31 (s, 1H). [M+H]=359.0.

Example 56-(4-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 5.34 (s, 2H), 7.06 (d, 1H), 7.27 (d, 2H), 7.37(d, 2H), 7.53 (d, 1H), 8.24 (s, 1H). [M+H]=317.0.

Example 66-Benzyl-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.64 (s, 3H), 5.42 (s, 2H), 6.70 (s, 1H), 7.34(m, 3H), 7.46 (d, 1H), 8.31 (s, 1H). [M+H]=297.0.

Example 76-([1,1′-Biphenyl]-4-ylmethyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.66 (s, 3H), 5.46 (s, 2H), 6.72 (s, 1H), 7.35(t, 1H), 7.42 (t, 2H), 7.54 (m, 6H), 8.32 (s, 1H). [M+H]=373.0.

Example 88-benzyl-6-(2-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 4.03 (s, 2H), 5.45 (s, 2H), 6.93 (m, 1H),7.3-7.1 (m, 8H), 7.37 (m, 1H), 8.22 (s, 1H). [M+H]=407.0.

Example 98-Benzyl-6-(3-chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 4.07 (s, 2H), 5.25 (s, 2H), 7.3-7.1 (m, 10H),8.20 (s, 1H). [M+H]=407.0.

Example 106-(2-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.67 (s, 2H), 5.59 (s, 2H), 6.70 (s, 1H), 7.02(d, 1H), 7.17 (t, 1H), 7.25 (t, 1H), 7.45 (d, 1H), 8.34 (s, 1H).[M+H]=331.0.

Example 116-(3-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.66 (s, 3H), 5.39 (s, 2H), 6.72 (s, 1H), 7.29(m, 3H), 7.44 (s, 1H), 8.32 (s, 1H). [M+H]=331.0.

Example 126-Benzyl-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CD₃OD) δ 2.50 (s, 3H), 5.43 (s, 2H), 7.21 (s, 1H), 7.32(m, 3H), 7.43 (m, 2H), 8.37 (s, 1H). [M+H]=297.0.

Example 136-(2-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.67 (s, 3H), 5.59 (s, 2H), 6.70 (s, 1H), 7.02(d, 1H), 7.16 (t, 1H), 7.25 (t, 1H), 7.45 (d, 1H), 8.34 (s, 1H).[M+H]=331.0.

Example 146-([1,1′-Biphenyl]-4-ylmethyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.52 (s, 3H), 5.43 (s, 2H), 7.21 (s, 1H), 7.35(t, 1H), 7.44 (t, 2H), 7.56 (m, 6H), 8.27 (s, 1H). [M+H]=373.0.

Example 156-(4-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.52 (s, 3H), 5.35 (s, 2H), 7.21 (s, 1H), 7.33(d, 2H), 7.40 (d, 2H), 8.27 (s, 1H). [M+H]=331.0.

Example 166-(3-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.46 (s, 3H), 5.29 (s, 2H), 7.15 (s, 1H), 7.25(m, 3H), 7.37 (s, 1H), 8.21 (s, 1H). [M+H]=331.0.

Example 176,8-Dibenzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 4.13 (s, 2H), 5.36 (s, 2H), 7.22 (s, 1H), 7.30(m, 8H), 7.43 (m, 2H), 8.26 (s, 1H). [M+H]=373.0.

Example 186-([1,1′-Biphenyl]-4-ylmethyl)-8-benzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 4.13 (s, 2H), 5.39 (s, 2H), 7.28 (m, 7H), 7.42(t, 2H), 7.55 (m, 6H), 8.26 (s, 1H). [M+H]=449.0.

Example 196-(2-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 0.92 (d, 6H), 1.56 (m, 3H), 2.79 (m, 2H), 5.56(s, 2H), 7.01 (d, 1H), 7.20 (t, 1H), 7.26 (m, 2H), 7.45 (d, 1H), 8.30(s, 1H). [M+H]=387.0.

Example 206-(3-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl3) δ 0.87 (d, 6H), 1.52 (m, 3H), 2.76 (m, 2H), 5.29(s, 2H), 7.22 (m, 4H), 7.38 (s, 1H), 8.21 (s, 1H). [M+H]=387.0.

Example 216-([1,1′-Biphenyl]-4-ylmethyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 0.95 (d, 6H), 1.59 (m, 3H), 2.82 (m, 2H), 5.44(s, 2H), 7.24 (s, 1H), 7.34 (m, 1H), 7.42 (t, 2H), 7.57 (m, 6H), 8.28(s, 1H). [M+H]=429.0.

Example 228-Benzyl-6-(4-chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 4.15 (s, 2H), 5.33 (s, 2H), 7.4-7.2 (m, 10H),8.28 (s, 1H). [M+H]=407.0.

Example 236-(4-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 0.88 (d, 6H), 1.55 (m, 3H), 2.75 (t, 2H), 5.28(s, 2H), 7.18 (s, 1H), 7.26 (d, 2H), 7.34 (d, 2H), 8.20 (s, 1H).[M+H]=387.0.

Example 246-Benzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 5.44 (s, 2H), 7.11 (d, 1H), 7.35 (m, 3H), 7.46(m, 2H), 7.57 (d, 1H), 8.29 (s, 1H). [M+H]=283.0.

Example 256-Benzyl-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 0.95 (d, 6H), 1.60 (m, 3H), 2.83 (m, 2H), 5.41(s, 2H), 7.24 (s, 1H), 7.37 (m, 3H), 7.48 (d, 2H), 8.28 (s, 1H).[M+H]=353.0.

Example 266-(4-Chlorobenzyl)-8,9-dimethylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.35 (s, 3H), 2.48 (s, 3H), 5.35 (s, 2H),7.41-7.42 (m, 4H), 8.49 (s, 1H). [M+H]=345.0.

Example 276-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 3.78 (s, 3H), 5.39 (s, 3H), 6.86-6.88 (m, 2H),7.12 (d, J=4.8 Hz, 1H), 7.44-7.45 (m, 2H), 7.57 (d, J=4.3 Hz, 1H), 8.29(s, 1H). [M+H]=313.1.

Example 286-(4-Methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.65 (s, 3H), 3.78 (s, 3H), 5.36 (s, 2H), 6.71(d, J=1.1 Hz, 1H), 6.87-6.85 (m, 2H), 7.44-7.43 (m, 2H), 8.31 (s, 1H).[M+H]=327.1.

Example 298-((1,4-Oxazepan-4-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

Step A: Methyl 5-bromo-3-cyanothiophen-2-ylcarbamate. To a solution ofcompound methyl 3-cyanothiophen-2-ylcarbamate (Example 1, Step A., 11.5g, 63 mmol) in acetic acid (500 mL) was added bromine (12 g, 75 mmol) atroom temperature. The solution was heated at 60° C. with stirring for 1h. The reaction mixture was concentrated and treated with water (500 mL)and extracted with EtOAc (3×300 mL). The combined organic layers weredried over sodium sulfate and concentrated to afford the title compound(14 g, 89%) as a solid. ¹H NMR (400 MHz CDCl₃) δ 3.89 (s, 3H), 6.90 (s,1H), 8.05 (s, 1H).

Step B: 8-Bromothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.The title compound was prepared in a manner analogous to Example 1, StepB. ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (s, 1H), 8.42 (s, 1H), 13.1 (br s,1H). [M+H]=270.9.

Step C:6-(4-Methoxybenzyl)-8-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.To mixture of8-bromo-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one(4.00 g, 10.2 mmol), potassium trifluoro(vinyl)borate (2.05 g, 15.3mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with DCM (417.5 mg, 0.51 mmol) in butan-1-ol (30 ml) was addedtriethylamine (1.43 ml, 0.01 mol). The resulting mixture was heated to100° C. Next morning the crude mixture was cooled to room temperature atwhich time the solvent was removed under reduced pressure. Purificationby FCC (SiO₂, 0-20% IPA in EtOAc) afforded the title compound as a brownsolid (2.90 g, 84%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.74 (s, 3H), 5.24-5.30(m, 1H), 5.34 (s, 2H), 5.52-5.63 (m, 1H), 6.94 (d, J=8.66 Hz, 2H), 7.41(d, J=8.53 Hz, 2H), 7.60 (s, 1H), 8.51 (s, 1H). [M+H]=339.2).

Step D:6-(4-Methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-8-carbaldehyde.6-(4-Methoxybenzyl)-8-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one(2.85 g; 8.42 mmol) was suspended in tetrahydrofuran (40 ml) and heatedwith a heat gun to effect dissolution. Similarly sodium periodate (4.14g; 19.4 mmol) was heated in water (20 ml) to effect dissolution. Theabove solutions were combined with vigorous stirring. While the stirredmixture was still about 40° C., osmium(VIII) oxide (2.06 ml, 2.50% w/w,0.21 mmol) was added and the mixture was stirred vigorously for 4 hours.The crude mixture was diluted with water (300 mL) and extracted with DCM(4×100). The organic layers were combined, dried over Na₂SO₄, filteredand concentrated. Purification by FCC (SiO₂, 0-30% IPA in EtOAc)afforded the title compound as a brown solid (1.82 g, 63%). ¹H NMR (400MHz, DMSO-d₆) δ 3.75 (s, 3H), 5.40 (s, 2H), 6.94 (d, J=8.66 Hz, 2H),7.45 (d, J=8.53 Hz, 2H), 8.58 (d, J=4.77 Hz, 2H), 9.95 (s, 1H).[M+H]=341.2.

Step E:8-((1,4-Oxazepan-4-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.To a mixture of6-(4-methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-8-carbaldehyde(50 mg, 0.15 mmol) and 1,4-oxazepane hydrochloride (30 mg, 0.22 mmol) inDCM (2 ml) was added triethylamine (25 μl, 0.18 mmol). After 5 minutesof stirring, sodium triacetoxyhydroborate (47 mg, 0.22 mmol) was added.The resulting mixture was stirred at room temperature. After 4 hours,the mixture was concentrated under reduced pressure. The resultingresidue was taken up in DMSO (2 mL), filtered and purified directly byreverse phase chromatography to yield the title compound (33 mg, 41%) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.98-2.16 (m, 2H), 3.14-3.60(m, 4H), 3.66-3.90 (m, 7H), 4.58-4.80 (m, 2H), 5.36 (s, 2H), 6.94 (d,J=8.53, 2H), 7.41 (d, J=8.53, 2H), 7.84 (br s, 1H), 8.55 (s, 1H).[M+H]=426.1.

Examples 30 thru 40 were made in a manner analogous to Example 29, withthe appropriate starting material and reagent substitutions.

Example 308-((Dimethylamino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.84 (s, 6H), 3.78 (s, 3H), 4.42 (s, 2H), 5.35(s, 2H), 6.87-6.88 (m, 2H), 7.44-7.46 (m, 2H), 7.65 (s, 1H), 8.30 (s,1H). [M+H]=370.1.

Example 316-(4-Methoxybenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.06-3.11 (m, 4H), 3.73 (s, 3H), 3.86-4.01(m, 4H), 4.56-4.59 (m, 2H), 5.34 (s, 2H), 6.92-6.94 (d, J=6.8 Hz, 2H),7.40-7.38 (d, J=6.8 Hz, 2H), 7.75 (s, 1H), 8.53 (s, 1H). [M+H]=412.2.

Example 326-(4-Methoxybenzyl)-8-((4-methylpiperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.28-2.38 (m, 2H), 2.79 (s, 3H), 2.98-3.11(m, 4H), 3.38-3.43 (m, 2H), 3.77 (s, 3H), 3.88 (s, 2H), 5.32 (s, 2H),6.90-6.92 (m, 2H), 7.34-7.36 (m, 2H), 7.55 (s, 1H), 8.55 (s, 1H).[M+H]=425.2.

Example 338-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.19-1.28 (m, 6H), 2.38-2.48 (m, 2H),3.32-3.42 (m, 2H), 3.77 (s, 3H), 4.01-4.09 (m, 2H), 4.32 (s, 2H), 4.78(s, 2H), 6.75-6.78 (m, 2H), 7.12-7.16 (m, 2H), 7.68 (s, 1H), 8.55 (s,1H). [M+H]=440.2

Example 348-((4-Ethyl-3-oxopiperazin-1-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.22 (t, J=7.22 Hz, 3H), 3.11-3.20 (m, 2H),3.48-3.63 (m, 6H), 3.82 (s, 3H), 4.15-4.22 (m, 2H), 5.40 (s, 2H), 6.92(d, J=8.66 Hz, 2H), 7.48 (d, J=8.53 Hz, 2H), 7.63 (s, 1H), 8.37 (s, 1H).[M+H]=453.2.

Example 356-(4-Methoxybenzyl)-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.92 (s, 3H), 3.19-3.30 (m, 4H), 3.63-3.72 (m,4H), 3.82 (s, 3H), 4.36 (s, 2H), 5.39 (s, 2H), 6.91 (d, J=8.53 Hz, 2H),7.48 (d, J=8.53 Hz, 2H), 7.68 (s, 1H), 8.35 (s, 1H). [M+H]=489.2.

Example 368-((2,2-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.43 (s, 6H), 3.37-3.51 (m, 2H), 3.82 (s, 3H),3.86-4.01 (m, 2H), 4.02-4.15 (m, 2H), 4.38-4.51 (m, 2H), 5.41 (s, 2H),6.91 (d, J=8.66 Hz, 2H), 7.51 (d, J=8.53 Hz, 2H), 7.68 (s, 1H), 8.34 (s,1H). [M+H]=440.2.

Example 378-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.19-2.32 (m, 1H), 2.34-2.55 (m, 1H),3.47-3.62 (m, 2H), 3.82 (s, 3H), 3.88-3.96 (m, 1H), 4.31-4.80 (m, 5H),5.31-5.48 (m, 2H), 6.91 (d, J=7.91 Hz, 2H), 7.50 (d, J=8.03 Hz, 2H),7.72 (s, 1H), 8.34 (s, 1H). [M+H]=424.2.

Example 388-(7-Oxa-2-azaspiro[3.5]nonan-2-ylmethyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.75-1.93 (m, 2H), 1.96-2.16 (m, 2H),2.94-3.20 (m, 4H), 3.58-3.68 (m, 4H), 3.82 (s, 3H), 4.50 (br s, 2H),5.38 (s, 2H), 6.91 (d, J=8.41 Hz, 2H), 7.48 (d, J=8.41 Hz, 2H), 7.75 (s,1H), 8.36 (s, 1H). [M+H]=452.1.

Example 398-(2-Oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.30-2.41 (m, 4H), 2.56-2.73 (m, 2H),3.46-3.71 (m, 4H), 3.82 (s, 3H), 4.37-4.54 (m, 4H), 5.39 (s, 2H), 6.91(d, J=8.66 Hz, 2H), 7.49 (d, J=8.66 Hz, 2H), 7.68 (s, 1H), 8.35 (s, 1H).[M+H]=452.1.

Example 407-((6-(4-Methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-8-yl)methyl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.89-2.09 (m, 2H), 2.79-2.86 (m, 1H),2.94-3.04 (m, 2H), 3.55-3.63 (m, 1H), 3.74 (s, 3H), 3.82 (d, J=5.27 Hz,3H), 3.88-3.95 (m, 1H), 4.32 (t, J=8.47 Hz, 1H), 5.34 (s, 2H), 6.94 (d,J=8.53 Hz, 2H), 7.39 (d, J=8.66 Hz, 2H), 7.48 (s, 1H), 8.50 (s, 1H).[M+H]=467.2.

Example 416-(4-Methoxybenzyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

Step A:6-(4-Methoxybenzyl)-8-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.To a mixture of8-bromo-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one(Example 29, product from Step C, 80 mg, 0.20 mmol) in toluene (2 ml)was added 1-methyl-5-(tributylstannyl)-3-(trifluoromethyl)-1H-pyrazole(135 mg, 0.31 mmol). The resulting mixture was heated to 100° C. for 16hours and cooled to room temperature. It was filtered through a pad ofcelite with DCM washing. The resulting filtrate was concentrated underreduced pressure, diluted in methanol, filtered and purified directlyvia reverse-phase HPLC to afford the title compound. ¹H NMR (400 MHz,CDCl₃) δ 3.83 (s, 3H), 4.07 (s, 3H), 5.43 (s, 2H), 6.70 (s, 1H), 6.93(d, J=8.66 Hz, 2H), 7.48 (d, J=8.66 Hz, 2H), 7.68 (s, 1H), 8.37 (s, 1H).[M+H]=461.1.

Example 42 was made in a manner analogous to Example 41, with theappropriate starting material and reagent substitutions.

Example 428-(3,5-Dimethylisoxazol-4-yl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.28 (s, 3H), 2.43 (s, 3H), 3.72 (s, 3H), 5.32(s, 2H), 6.82 (d, J=8.66 Hz, 2H), 7.38 (d, J=8.91 Hz, 3H), 8.25 (s, 1H).[M+H]=408.0.

Example 436-(4-Methoxybenzyl)-9-methyl-8-(pyrrolidin-1-ylmethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

Step A:6-(4-Methoxybenzyl)-9-methyl-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-8-carbaldehyde.Phosphorus oxychloride (1.47 ml, 15.8 mmol) was added toN,N-dimethylformamide (13 ml) and the mixture was stirred for 20minutes.6-(4-Methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one(1.29 g, 3.94 mmol) was added as a solid and the mixture was heated at90° C. for 45 minutes. The mixture was cooled to room temperature andpoured into a mixture of ice (30 mL) and potassium carbonate (5 g).After the ice had melted the pH was 8-9. The mixture was extracted withDCM (3×30 mL) and the combined extracts were washed with brine (30 mL),dried (MgSO₄) and concentrated under vacuum. Purification by FCC (SiO₂,20-100% EtOAc in hexanes) the title compound (0.87 g, 62%) as a yellowpowder. ¹H NMR (400 MHz, CDCl₃) δ 3.01 (s, 3H), 3.78 (s, 3H), 5.38 (s,2H), 6.86-6.88 (m, 2H), 7.44-7.46 (m, 2H), 8.33 (s, 1H), 10.12 (s, 1H).[M+H]=355.0.

Step B:6-(4-Methoxybenzyl)-9-methyl-8-(pyrrolidin-1-ylmethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.6-(4-Methoxybenzyl)-9-methyl-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-8-carbaldehyde(48 mg, 0.14 mmol) was suspended in N,N-dimethylformamide (0.5 ml) andmethanol (0.2 ml) and treated with pyrrolidine (0.075 ml, 0.90 mmol).The mixture was stirred for 30 minutes and sodium cyanoborohydride (20mg, 0.32 mmol) and acetic acid (0.050 ml) were added and stirring wascontinued for 18 hours. The mixture was diluted with DMF and purified byHPLC (0-75% ACN in water) to afford 18 mg (25%) of 4 as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 1.84-1.86 (m, 2H), 2.03-2.05 (m, 2H), 2.67(s, 3H), 3.10-3.12 (m, 2H), 3.41-3.43 (m, 2H), 3.73 (s, 3H), 4.64 (d,J=4.7 Hz, 2H), 5.32 (s, 2H), 6.91-6.93 (m, 2H), 7.36-7.38 (m, 2H), 8.56(s, 1H), 9.93 (br s, 1H). [M+H]=410.1.

Examples 44 thru 75 were made in a manner analogous to Example 43, withthe appropriate starting material and reagent substitutions.

Example 446-(4-Methoxybenzyl)-9-methyl-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.70 (s, 3H), 3.50-3.00 (m, 4H), 3.78 (s, 3H),3.98-3.96 (m, 4H), 4.36 (s, 2H), 5.32 (s, 2H), 6.88-6.86 (m, 2H),7.46-7.44 (m, 2H), 8.31 (s, 1H). [M+H]=426.1.

Example 458-((Dimethylamino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.71 (s, 3H), 2.85 (s, 6H), 3.78 (s, 3H), 4.42(s, 2H), 5.33 (s, 2H), 6.86-6.87 (m, 2H), 7.43-7.45 (m, 2H), 8.32 (s,1H). [M+H]=384.1.

Example 468-((Cyclopropyl(methyl)amino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 0.85-0.90 (m, 2H), 1.35-1.45 (m, 2H),2.40-2.48 (m, 1H), 2.74 (s, 3H), 2.88 (s, 3H), 3.78 (s, 3H), 4.54 (s,2H), 6.85-6.90 (m, 2H), 6.40-7.45 (m, 2H), 8.33 (s, 1H). [M+H]=410.1.

Example 478-((4-Hydroxypiperidin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.50-1.53 (m, 1H), 1.77-1.80 (m, 2H),1.95-1.98 (m, 1H), 2.65-2.67 (m, 3H), 3.03-3.05 (m, 1H), 3.20-3.59 (m,5H), 3.73 (s, 3H), 4.54-4.61 (m, 2H), 5.33 (s, 2H), 6.92-6.93 (m, 2H),7.36-7.38 (m, 2H), 8.56 (s, 1H), 9.48 (br s, 1H). [M+H]=440.2.

Example 488-((Benzyl(2-hydroxyethyl)amino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.57 (s, 3H), 3.63-3.65 (m, 4H), 3.72 (s,3H), 4.20-4.60 (m, 4H), 5.32 (s, 2H), 6.90-6.93 (m, 2H), 7.36-7.40 (m,7H), 8.53 (s, 1H). [M+H]=490.2.

Example 496-(4-Methoxybenzyl)-9-methyl-8-(piperazin-1-ylmethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.55 (s, 3H), 2.67 (br s, 4H), 3.09 (br s,4H), 3.73 (s, 3H), 3.80 (br s, 2H), 5.30 (s, 2H), 6.90-6.93 (m, 2H),7.34-7.36 (m, 2H), 8.51 (s, 1H), 8.61 (br s, 2H). [M+H]=425.1.

Example 506-(4-Methoxybenzyl)-9-methyl-8-((((3-methyloxetan-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.31 (s, 3H), 2.67 (s, 3H), 3.73 (s, 3H),4.22 (d, J=5.1 Hz, 2H), 4.38 (d, J=5.0 Hz, 2H), 4.60 (br s, 2H), 5.34(s, 2H), 6.90-6.93 (m, 2H), 7.34-7.36 (m, 2H), 8.56 (s, 1H), 8.83 (br s,2H). [M+H]=440.1.

Example 518-((4-Acetylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.03 (s, 3H), 2.63 (s, 3H), 2.85-3.15 (m,4H), 3.56 (br s, 4H), 3.73 (s, 3H), 4.45-4.65 (m, 2H), 5.32 (s, 2H),6.91-6.93 (m, 2H), 7.36-7.38 (m, 2H), 8.55 (s, 1H). [M+H]=467.2.

Example 526-(4-Methoxybenzyl)-9-methyl-8-(((pyridin-3-ylmethyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.63 (s, 3H), 3.72 (s, 3H), 4.30 (s, 2H),4.47 (s, 2H), 5.32 (s, 2H), 6.90-6.93 (m, 2H), 7.34-7.36 (m, 2H), 7.52(dd, J=6.3, 3.9 Hz, 1H), 7.94-7.96 (m, 1H), 8.55 (s, 1H), 8.63 (dd,J=3.9, 1.2 Hz, 1H), 8.68 (d, J=1.5 Hz, 1H), 9.34 (br s, 2H).[M+H]=447.1.

Example 536-(4-Methoxybenzyl)-9-methyl-8-((3-oxopiperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.59 (s, 3H), 2.95 (br, 2H), 3.72 (s, 3H),3.24 (br s, 4H), 3.33 (br s, 2H), 5.32 (s, 2H), 6.90-6.92 (m, 2H),7.35-7.37 (m, 2H), 8.07 (br s, 1H), 8.53 (s, 1H). [M+H]=439.1.

Example 546-(4-Methoxybenzyl)-9-methyl-8-((methyl((tetrahydrofuran-2-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.45-1.52 (m, 1H), 1.78-1.87 (m, 2H),1.98-2.04 (m, 1H), 2.65 (s, 3H), 2.79 (s, 3H), 2.96-3.00 (m, 1H),3.12-3.16 (m, 1H), 3.28-3.32 (m, 1H), 3.66-3.72 (m, 2H), 3.73 (s, 3H),3.78-3.82 (m, 1H), 4.22-4.25 (m, 1H), 4.50-4.66 (m, 2H), 5.30-5.38 (m,2H), 6.90-6.93 (m, 2H), 7.36-7.37 (m, 2H), 8.56 (s, 1H), 9.70-9.90 (m,1H). [M+H]=454.1.

Example 558-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.10 (d, J=4.4 Hz, 6H), 2.63 (s, 3H),2.64-2.68 (m, 2H), 3.30-3.52 (m, 4H), 3.72 (s, 3H), 4.55 (br s, 2H),5.30 (s, 2H), 6.91-6.93 (m, 2H), 7.36-7.38 (m, 2H), 8.55 (s, 1H), 10.18(br s, 1H). [M+H]=454.1.

Example 568-(Isoindolin-2-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.69 (s, 3H), 3.73 (s, 3H), 4.60 (br s, 4H),4.87 (br s, 2H), 5.34 (s, 2H), 6.92-6.93 (m, 2H), 7.37-7.39 (m, 6H),8.57 (s, 1H), 11.05 (br s, 1H). [M+H]=458.1.

Example 578-((Cyclopropylamino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.75-0.80 (m, 4H), 2.65 (s, 3H), 2.71-2.73(m, 1H), 3.73 (s, 3H), 4.49 (s, 2H), 5.32 (s, 2H), 6.90-6.93 (m, 2H),7.34-7.36 (m, 2H), 8.54 (s, 1H), 9.05 (br s, 1H). [M+H]=396.1.

Example 58(S)-6-(4-Methoxybenzyl)-8-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.68-1.70 (m, 1H), 1.80-1.83 (m, 1H),2.00-2.02 (m, 1H), 2.14-2.16 (m, 1H), 2.66 (s, 3H), 3.26 (s, 3H),3.46-3.48 (m, 3H), 3.72 (s, 3H), 3.75 (br s, 1H), 4.55 (d, J=11.1, 1H),4.77 (d, J=11.3 Hz, 1H), 5.30 (d, J=12.9 Hz, 1H), 5.37 (d, J=13.0 Hz,1H), 6.90-6.93 (m, 2H), 7.36-7.38 (m, 2H), 8.56 (s, 1H), 9.70 (br s,1H). [M+H]=454.2.

Example 596-(4-Methoxybenzyl)-9-methyl-8-((methyl((tetrahydrofuran-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.51-1.54 (m, 1H), 2.02-2.05 (m, 1H), 2.66(s, 3H), 2.75 (s, 3H), 3.14-3.16 (m, 1H), 3.32-3.37 (m, 1H), 3.60-3.71(m, 3H), 3.73 (s, 3H), 3.74-3.86 (m, 2H), 4.56-4.64 (m, 2H), 5.32-5.34(m, 2H), 5.90-5.92 (m, 2H), 7.36-7.37 (m, 2H), 8.56 (s, 1H), 9.56 (br s,1H). [M+H]=454.3.

Example 602-(((6-(4-Methoxybenzyl)-9-methyl-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-8-yl)methyl)(methyl)amino)-N,N-dimethylacetamide

¹H NMR (400 MHz, DMSO-d₆) δ 2.66 (s, 3H), 2.78 (s, 3H), 2.880 (s, 3H),2.885 (s, 3H), 3.73 (s, 3H), 4.19 (br s, 2H), 4.52 (br s, 2H), 5.34 (s,2H), 6.92-6.94 (m, 2H), 7.37-7.38 (m, 2H), 8.56 (s, 1H), 9.70 (br s,1H). [M+H]=339.1

Example 618-((1,4-Oxazepan-4-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.13 (s, 3H), 3.24-3.72 (m, 6H), 3.73 (s,3H), 3.85-3.87 (m, 2H), 4.66 (br s, 2H), 5.33 (s, 2H), 6.91-6.94 (m,2H), 7.36-7.38 (m, 2H), 8.56 (s, 1H), 9.83 (br s, 1H). [M+H]=440.2.

Example 626-(4-Methoxybenzyl)-9-methyl-8-((4-methylpiperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.58 (s, 4H), 2.81 (s, 4H), 3.03 (br s, 5H),3.39 (br s, 3H), 3.75 (s, 7H), 3.80 (s, 5H), 5.31 (s, 2H), 6.93 (d,J=8.66 Hz, 2H), 7.36 (d, J=8.53 Hz, 2H), 8.50 (s, 1H). [M+H]=440.2.

Example 636-(4-Methoxybenzyl)-9-methyl-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl3 and methanol-d4) δ 2.45 (s, 3H), 2.69 (s, 3H),2.76 (br s, 4H), 3.23 (br s, 4H), 3.60 (s, 3H), 3.88 (s, 2H), 5.17 (s,2H), 6.59-6.79 (m, 2H), 7.25 (d, J=8.78 Hz, 2H), 8.13 (s, 1H).[M+H]=503.2.

Example 648-((4-Isopropylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.41 (d, J=5.77 Hz, 6H), 2.50-2.73 (m, 3H),3.37 (br s, 6H), 3.53 (d, J=5.27 Hz, 3H), 3.79 (br s, 3H), 4.07 (br s,2H), 5.31 (br s, 2H), 6.87 (d, J=7.15 Hz, 2H), 7.41 (d, J=7.53 Hz, 2H),8.31 (br s, 1H). [M+H]=467.3.

Example 658-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.24 (d, J=11.54 Hz, 1H), 2.40 (br s, 1H),2.73 (s, 3H), 3.79 (s, 3H), 3.80 (s, 1H), 3.89 (d, J=10.04 Hz, 1H), 4.39(br s, 2H), 4.46-4.54 (m, 1H), 4.56-4.64 (m, 1H), 4.73 (br s, 1H), 5.34(s, 2H), 6.85-6.90 (m, 2H), 7.46 (d, J=8.66 Hz, 2H), 8.32 (s, 1H).[M+H]=438.2.

Example 668-((4-Ethyl-3-oxopiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.10 (t, J=7.22 Hz, 3H), 2.59 (s, 3H), 3.12(br s, 2H), 3.34-3.47 (m, 3H), 3.52 (s, 3H), 3.70 (s, 3H), 4.11 (s, 2H),5.26 (s, 2H), 6.79 (d, J=8.66 Hz, 2H), 7.36 (d, J=8.66 Hz, 2H), 8.25 (s,1H). [M+H]=467.2.

Example 678-(8-Oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.08-2.21 (m, 2H), 2.32-2.41 (m, 2H), 2.70 (s,3H), 3.06 (dd, J=11.98, 2.57 Hz, 2H), 3.46 (d, J=11.92 Hz, 2H), 3.79 (s,3H), 4.43 (s, 2H), 4.52 (br s, 2H), 5.36 (s, 2H), 6.86-6.91 (m, 2H),7.46 (d, J=8.66 Hz, 2H), 8.33 (s, 1H). [M+H]=452.2.

Example 688-((2-Ethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 0.98 (t, J=7.47 Hz, 3H), 1.46-1.60 (m, 2H),2.53 (t, J=10.85 Hz, 1H), 2.71 (s, 3H), 2.86 (d, J=9.29 Hz, 1H), 3.48(dd, J=18.89, 11.86 Hz, 2H), 3.79 (s, 3H), 3.87 (dt, J=10.29, 5.40 Hz,1H), 4.03-4.12 (m, 2H), 4.41 (s, 2H), 5.35 (s, 2H), 6.88 (d, J=8.66 Hz,2H), 7.45 (d, J=8.66 Hz, 2H), 8.32 (s, 1H). [M+H]=454.2.

Example 698-((2,2-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.40 (br s, 5H), 2.71 (s, 3H), 2.79-3.36 (m,4H), 3.79 (3, 3H), 3.93-4.13 (m, 2H), 4.44 (br s, 2H), 5.35 (s, 2H),6.80-6.94 (m, 2H), 7.46 (d, J=8.66 Hz, 2H), 8.32 (s, 1H). [M+H]=454.2.

Example 706-(4-Methoxybenzyl)-9-methyl-8-((2-methylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J=6.27 Hz, 3H), 2.51 (t, J=11.11 Hz,1H), 2.71 (s, 3H), 2.78-2.93 (m, 1H), 3.48 (dd, J=18.01, 11.73 Hz, 2H),3.79 (s, 3H), 3.95-4.19 (m, 3H), 4.40 (s, 2H), 5.34 (s, 2H), 6.82-6.97(m, 2H), 7.45 (d, J=8.66 Hz, 2H), 8.32 (s, 1H). [M+H]=440.2.

Example 716-(4-Methoxybenzyl)-9-methyl-8-((3-methylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.57 (d, J=6.65 Hz, 3H), 2.72 (s, 3H), 2.88(br s, 1H), 3.28 (br s, 2H), 3.44-3.61 (m, 1H), 3.79 (s, 3H), 3.82-3.92(m, 1H), 3.92-4.02 (m, 2H), 4.04-4.14 (m, 1H), 4.23 (d, J=12.17 Hz, 1H),5.21-5.33 (m, 1H), 5.35-5.54 (m, 1H), 6.83-6.97 (m, 2H), 7.45 (d, J=8.66Hz, 2H), 8.33 (s, 1H). [M+H]=440.2.

Example 728-(((3R,5S)-3,5-Dimethylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.02 (br s, 6H), 2.00 (t, J=11.61 Hz, 2H),2.25 (br s, 3H), 2.61 (d, J=11.92 Hz, 2H), 2.96 (br s, 2H), 3.40 (br s,2H), 3.45 (br s, 3H), 5.01 (br s, 2H), 6.46-6.60 (m, 2H), 7.08 (d,J=8.03 Hz, 2H), 7.94 (br s, 1H), 8.58 (br s, 1H), 9.83 (br s, 1H).[M+H]=453.3.

Example 738-((3,4-Dimethylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.51 (d, J=5.40 Hz, 3H), 2.66 (s, 3H), 2.90(br s, 3H), 3.17-3.70 (m, 7H), 3.79 (s, 3H), 4.17 (br s, 2H), 5.23-5.31(m, 1H), 5.32-5.42 (m, 1H), 6.87 (d, J=8.66 Hz, 2H), 7.41 (d, J=8.53 Hz,2H), 8.32 (s, 1H). [M+H]=453.3.

Example 746-(4-Methoxybenzyl)-9-methyl-8-((3,3,4-trimethylpiperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.36 (br s, 3H), 1.44 (br s, 3H), 2.60 (s,3H), 2.74 (s, 3H), 2.76-2.83 (m, 2H), 2.97-3.08 (m, 2H), 3.15 (br s,1H), 3.46 (d, J=11.54 Hz, 1H), 3.79 (s, 3H), 3.80 (br s, 2H), 5.17-5.27(m, 1H), 5.41-5.57 (m, 1H), 6.86 (d, J=8.66 Hz, 2H), 7.42 (d, J=8.66 Hz,2H), 8.32 (s, 1H). [M+H]=467.3.

Example 75(S)-8-((Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.00-2.30 (m, 4H), 2.66 (s, 3H), 3.31-3.68 (m,9H), 3.79 (s, 3H), 4.03-4.37 (m, 2H), 5.30 (d, J=15.18 Hz, 1H), 5.36 (d,J=15.43 Hz, 1H), 6.84-6.93 (m, 2H), 7.42 (d, J=8.66 Hz, 2H), 8.32 (s,1H). [M+H]=465.3.

Example 768-Bromo-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

8-Bromo-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.N-Bromopyrrolidine-2,5-dione (0.57 g, 3.2 mmol) was added to a stirredsuspension of6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one(1.01 g, 3.09 mmol) in acetonitrile (20 ml) and the mixture was stirredfor 14 hours. The crude reaction mixture was concentrated under reducedpressure and dissolved in DCM. Purification by FCC (SiO₂, 10-100% EtOAcin hexanes) afforded the title compound (1.31 g, 100%) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 2.60 (s, 3H), 3.79 (s, 3H), 5.31 (s, 2H),6.87-6.89 (m, 2H), 7.40-7.41 (m, 2H), 8.31 (s, 1H). [M+H]=404.9.

Example 778-(Hydroxymethyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

8-(Hydroxymethyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.Sodium borohydride (25 mg, 0.66 mmol) was added to a stirred suspensionof6-(4-methoxybenzyl)-9-methyl-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-8-carbaldehyde(Example 43, product from Step A, 65 mg, 0.18 mmol) in methanol (3 ml)and the mixture was stirred for 2 hours. Saturated sodium bicarbonate(0.2 mL) was added and the mixture was stirred for 20 minutes,concentrated under reduced pressure, dissolved in DCM, filtered andpurified by preparative HPLC to afford 44 mg (68%) of 77 as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 2.62 (s, 3H), 3.78 (s, 3H), 4.84 (s,2H), 5.33 (s, 2H), 6.85-6.87 (m, 2H), 7.42-7.44 (m, 2H), 8.30 (s, 1H).[M+H]=357.0.

Example 789-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

Step A. 2-Amino-4-oxo-4,5-dihydrothiophene-3-carbonitrile. To a solutionof malonitrile (80 g, 1.21 mol) and chloro-acetyl chloride (137 g, 1.21mol) in DMF (650 mL) was added Et₃N (371 mL, 2.67 mol) dropwise at 0° C.The reaction mixture was warmed to room temperature and stirred for 2hours. The reaction mixture was cooled to 0° C., and an aq. solution of(NH₄)₂S (16-20%, 535 mL, 1.33 mol) was added dropwise, and stirred atroom temperature overnight. The mixture was poured into ice-water (1.5L) and the precipitate formed was filtered off and dried to provide thetitle compound (166 g, 49%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.2 (s, 2H), 3.79 (s, 2H).

Step B: Methyl (3-cyano-4-oxo-4,5-dihydrothiophen-2-yl)carbamate. Methylchloroformate (55 g, 0.58 mol) was added to a stirred solution of2-amino-4-oxo-4,5-dihydrothiophene-3-carbonitrile (68 g, 0.49 mol) andTEA (147 g, 1.45 mol) in DCM (1.0 L) at 0° C. After the addition, themixture was warmed to 25° C. and stirred overnight. The reaction wastreated with DCM-methanol (20:1, 2.0 L) and 2 N hydrochloric acid (1.5L). The resulting mixture was filtered and the resulting solid wasfurther extracted with DCM-methanol (20:1, 1500 mL×3). The combinedorganic extracts were dried (Na₂SO₄) and concentrated under reducedpressure to give a brown solid. The solid was washed with tert-butylmethyl ether (1500 mL) and concentrated under reduced pressure to givethe title compound (80 g, 83%) as a brown solid, which was used in nextstep without purification.

Step C: 4-Cyano-5-((methoxycarbonyl)amino)thiophen-3-yltrifluoromethanesulfonate. Triethylamine (329 mL, 2.36 mmol) was addedto a suspension of methyl(3-cyano-4-oxo-4,5-dihydrothiophen-2-yl)carbamate (156 g, 0.788 mol) inDCM (1.5 L). Trifluoromethanesulfonic anhydride (267 g, 0.945 mol) wasadded drop-wise at 0° C. After addition, the mixture was warmed to roomtemperature and stirred overnight. The mixture was concentrated undervacuum. Purification by FCC (SiO₂, 5-50% EtOAc in petroleum ether)afforded the title compound (100 g, 38%) as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 3.86 (s, 3H), 6.7 (s, 1H).

Step D:5-Oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-9-yltrifluoromethanesulfonate. A solution of4-cyano-5-((methoxycarbonyl)amino)thiophen-3-yltrifluoromethanesulfonate (2.0 g, 6.1 mmol), formic acid hydrazide (0.73g, 12 mmol), tri-n-propylamine (1 mL) and 2-methoxyethanol (15 mL) washeated at 160° C. for 10 minutes via microwave. The mixture wascombined, concentrated, and the residue was purified by HPLC to give thetitle compound (0.31 g, 15%) as a pale solid. ¹H NMR (400 MHz, DMSO-d₆)δ 7.32 (s, 1H), 8.31 (s 1H). [M+H]=340.9.

Step E:6-(4-Methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-9-yltrifluoromethanesulfonate. To a solution of5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-9-yltrifluoromethanesulfonate (3.00 g, 8.82 mmol) in DMF (60.0 mL) was added1-(chloromethyl)-4-methoxybenzene (2.39 ml, 17.6 mmol), potassium iodide(0.73 g, 4.41 mmol) and potassium carbonate (3.66 g, 26.5 mmol). Theresulting mixture was heated to 60° C. After 16 hours the crude mixturewas allowed to cool to room temperature at which time water was added(100 mL) and the organics were extracted with EtOAc (75 mL×3). Theorganic layers were combined, dried, filtered and concentrated.Purification by FCC (SiO₂, 10-80% EtOAc in hexanes) afforded the titlecompound (3.25 g, 80%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 3.83(s, 3H), 5.40 (s, 2H), 6.93 (d, J=8.66 Hz, 2H), 7.05 (s, 1H), 7.46 (d,J=8.78 Hz, 2H), 8.41 (s, 1H). [M+H]=461.0.

Step F:6-(4-Methoxybenzyl)-9-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.To mixture of6-(4-methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-9-yltrifluoromethanesulfonate (1.68 g, 3.65 mmol), potassiumtrifluoro(vinyl)borate (0.73 g, 5.47 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith DCM (149 mg, 0.18 mmol) in butan-1-ol (15 ml) was addedtriethylamine (0.51 ml, 3.65 mmol). The resulting mixture was heated to100° C. After 16 hours, the mixture was cooled to room temperature atwhich time the solvent was removed under reduced pressure. Purificationby FCC (SiO₂, 0-30% IPA in EtOAc) afforded the title compound (0.85 g,69%) as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.74 (s, 3H), 5.35 (s,2H), 5.45 (d, J=11.29 Hz, 1H), 6.05 (d, J=17.69 Hz, 1H), 6.93 (d, J=8.53Hz, 2H), 7.39 (d, J=8.66 Hz, 2H), 7.41-7.50 (m, 1H), 7.64 (s, 1H), 8.53(s, 1H). [M+H]=339.2.

Step G:6-(4-Methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9-carbaldehyde.6-(4-Methoxybenzyl)-9-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one(850 mg, 2.51 mmol) was suspended in tetrahydrofuran (17 ml) and heatedwith a heat gun to effect dissolution. Similarly sodium periodate (1.24g, 5.78 mmol) was heated in water (8.5 ml) to effect dissolution. Theabove solutions were combined with vigorous stirring. While the stirredmixture was at 40° C., osmium(VIII) oxide (737 μl, 2.50% w/w, 0.08 mmol)was added and the mixture was stirred vigorously for 4 hours. It wasdiluted with water (300 mL) and the resulting solids were collected viavacuum filtration to yield the aldehyde (0.58 g, 68%) as pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.74 (s, 3H), 5.42 (s, 2H), 6.94 (d,J=8.66 Hz, 2H), 7.42 (d, J=8.53 Hz, 2H), 8.29 (s, 1H), 8.61 (s, 1H),10.58 (s, 1H). [M+H]=341.1.

Step H:9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.To a mixture of6-(4-methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9-carbaldehyde(35 mg, 0.10 mmol) and (2S,6R)-2,6-dimethylmorpholine (24 mg, 0.21 mmol)in DMF was added sodium cyanoborohydride (9.7 mg, 0.15 mmol). Theresulting mixture was stirred at room temperature. After 16 hours, thecrude mixture was filtered and purified directly via reverse-phase HPLC.Product fractions were concentrated under reduced pressure to yield 78(56 mg, 47%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.21 (d, J=6.27Hz, 6H), 2.69-2.78 (m, 2H), 3.36-3.41 (m, 2H), 3.83 (s, 3H), 4.04-4.15(m, 2H), 4.82 (s, 2H), 5.41 (s, 2H), 6.92 (d, J=8.66 Hz, 2H), 7.49 (d,J=8.66 Hz, 2H), 7.83-7.92 (m, 1H), 8.33 (s, 1H). [M+H]=440.2.

Example 796-(4-Chlorobenzyl)-8,9-dimethylfuro[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

Step A: Methyl (3-cyano-4,5-dimethylfuran-2-yl)carbamate. The titlecompound was prepared in a manner analogous to Example 1, Step A. ¹H NMR(400 MHz, DMSO-d₆) δ 1.94 (s, 3H), 2.15 (s, 3H), 3.70 (s, 3H), 10.78 (s,1H). [M+H]=195.1.

Step B:8,9-Dimethylfuro[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one. Thetitle compound was prepared in a manner analogous to Example 1 Step B.¹H NMR (400 MHz, DMSO-d₆) δ 2.21 (s, 3H), 2.29 (s, 3H), 8.31 (s, 1H).[M+H]=205.1.

Step 8.3:6-(4-Chlorobenzyl)-8,9-dimethylfuro[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one.The title compound was prepared in a manner analogous to Example 1, StepC. ¹H NMR (400 MHz, DMSO-d₆) δ 2.24 (s, 3H), 2.32 (s, 3H), 5.32 (s, 2H),7.40-7.44 (m, 4H), 8.40 (s, 1H). [M+H]=329.0.

Example 80 tert-Butyl6-(4-methoxybenzyl)-5-oxo-5,6,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9(8H)-carboxylate

Step A: tert-Butyl2-amino-3-cyano-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate.Prepared from tert-butyl 4-oxo-1-piperidinecarboxylate, as described inWang et al., Synlett., 2010, 9, 1351-1354.

Step B: tert-Butyl3-cyano-2-((methoxycarbonyl)amino)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate.The title compound was prepared in a manner analogous to Example 1, StepA. ¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (t, J=7.09 Hz, 3H), 1.43 (s, 9H),2.53-2.61 (m, 2H), 3.61 (t, J=5.65 Hz, 2H), 4.21 (q, J=7.15 Hz, 2H),4.44 (s, 2H), 11.32 (br s, 1H). [M+H]=251.2).

Step C: tert-Butyl5-oxo-5,6,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9(8H)-carboxylate.The title compound was prepared in a manner analogous to Example 1, StepB. ¹H NMR (400 MHz, DMSO-d₆) δ 1.45 (s, 9H), 2.93-3.02 (m, 2H), 3.70 (t,J=5.65 Hz, 2H), 4.59 (s, 2H), 8.44 (s, 1H). [M+H]=348.2).

Step D: tert-Butyl6-(4-methoxybenzyl)-5-oxo-5,6,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9(8H)-carboxylate.The title compound was prepared in a manner analogous to Example 1, StepC. ¹H NMR (400 MHz, DMSO-d₆) δ 1.43 (s, 9H), 2.99 (br s, 2H), 3.68 (t,J=5.4, 2H), 3.74 (s, 3H), 4.57 (br s, 2H), 5.31 (s, 2H), 6.92 (d,J=8.53, 2H), 7.36 (d, J=8.53, 2H), 8.43-8.54 (m, 1H). [M+H]=

Examples 81, 83 thru 98 were made in a manner analogous to Example 80,with the appropriately substituted amino-cyano-thiene starting materialsand reagent substitutions.

Example 816-(2-Chlorobenzyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.83 (m, 4H), 2.64 (m, 2H), 2.99 (m, 2H), 5.49(s, 2H), 6.92 (d, 1H), 7.21 (t, 1H), 7.10 (t, 1H), 7.37 (d, 1H), 8.25(s, 1H). [M+H]=371.0.

Example 824-(4-Methoxybenzyl)-2-(morpholinomethyl)pyrazolo[1,5-c]thieno[3,2-e]pyrimidin-5(4H)-one

Step A: 5-Nitro-4-(1H-pyrazol-3-yl)thiophene-2-carbaldehyde. A flaskcontaining 4-bromo-5-nitrothiophene-2-carbaldehyde (1.00 g, 4.24 mmol),(1H-pyrazol-5-yl)boronic acid (510 mg, 4.56 mmol), ethyleneglycoldimethyl ether (20 mL), triethylamine (1.80 mL), water (2.00 mL) andbis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM(340 mg, 0.42 mmol) was evacuated and purged with nitrogen twice, thenheated at 80° C. under nitrogen for 4 h. The reaction was cooled to roomtemperature, poured into a saturated solution of ammonium chloride (20mL), extracted with EtOAc (3×10 mL), combined organics washed with asaturated solution of ammonium chloride (30 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by FCC (SiO₂, 5-100%EtOAc in hexanes) afforded the title compound as a yellow oil (950 mg,28%). ¹H NMR (400 MHz, DMSO-d₆) δ 6.99 (s, 1H), 7.94 (s, 1H), 8.42 (s,1H), 10.07 (s, 1H).

Step B: 5-Amino-4-(1H-pyrazol-3-yl)thiophene-2-carbaldehyde.5-Nitro-4-(1H-pyrazol-5-yl)thiophene-2-carbaldehyde (40 mg, 0.18 mmol)was dissolved in absolute ethanol (4 mL). A saturated solution of sodiumhydrosulfite in water was added dropwise until complete consumption ofthe starting material (10 minutes). Water (30 mL) added, the aqueouslayer extracted with EtOAc (3×10 mL), and the resulting organics weredried (Na₂SO₄) and concentrated under reduced pressure. Purification byFCC (SiO₂, 5-100% EtOAc in hexanes) afforded the title compound as apowder (11 mg, 42%). ¹H NMR (400 MHz, DMSO-d₆) δ 6.60 (d, J 2.3 Hz, 1H),7.80 (d, J 2.3 Hz, 1H), 8.02 (s, 1H), 9.49 (s, 1H).

Step C:5-Oxo-4,5-dihydropyrazolo[1,5-c]thieno[3,2-e]pyrimidine-2-carbaldehyde.5-Amino-4-(1H-pyrazol-5-yl)thiophene-2-carbaldehyde (12 mg, 0.06 mmol)and bis(trichloromethyl) carbonate (55 mg, 0.19 mmol) were dissolved intoluene (3 mL) and THF (0.5 mL), and the reaction heated in a sealedtube at 100° C. for 3 h. The reaction was cooled to room temperature,hexanes (10 mL) added, suspension stirred at room temperature for 30min, precipitate washed with additional hexanes (10 mL), dried underreduced pressure to afford the title compound as a powder (11 mg, 81%).¹H NMR (400 MHz, DMSO-d₆) δ 6.99 (s, 1H), 8.12 (s, 1H), 8.45 (s, 1H),9.93 (s, 1H), 13.06 (s, 1H).

Step D:4-(4-Methoxybenzyl)-5-oxo-4,5-dihydropyrazolo[1,5-c]thieno[3,2-e]pyrimidine-2-carbaldehyde.5-Oxo-4,5-dihydropyrazolo[1,5-c]thieno[3,2-e]pyrimidine-2-carbaldehyde(30 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (3.0 mL),1-(chloromethyl)-4-methoxybenzene (0.04 ml, 0.27 mmol) and potassiumcarbonate (57 mg, 0.41 mmol) were added and the reaction stirred at 60°C. for 5 h. Reaction poured into saturated ammonium chloride solution(20 mL), extracted with EtOAc (3×10 mL), organics washed with saturatedammonium chloride solution (20 mL), dried (Na₂SO₄) and concentratedunder reduced pressure. Purification by FCC (SiO₂, EtOAc in hexanes)afforded the title compound as a powder (16 mg, 89%). ¹H NMR (400 MHz,acetone-d6) δ 3.80 (s, 3H), 5.46 (s, 2H), 6.92-7.00 (m, 3H), 7.51 (d,J=8.66 Hz, 2H), 8.08 (d, J=1.76 Hz, 1H), 8.37, (s, 1H), 9.94 (s, 1H).

Step E:4-(4-Methoxybenzyl)-2-(morpholinomethyl)pyrazolo[1,5-c]thieno[3,2-e]pyrimidin-5(4H)-one.4-(4-Methoxybenzyl)-5-oxo-4,5-dihydropyrazolo[1,5-c]thieno[3,2-e]pyrimidine-2-carbaldehyde(16 mg, 0.05 mmol) was dissolved in DCM (2 mL). Morpholine (0.020 mL,0.24 mmol) and acetic acid (0.04 mL) were added and the mixture wasstirred for 10 minutes before the addition of sodium cyanoborohydride (6mg, 0.09 mmol). The reaction was stirred at room temperature for anadditional 15 hours, poured into a saturated solution of aqueous sodiumbicarbonate (20 mL), and extracted with EtOAc (3×10 mL). The combinedextracts were dried (Na₂SO₄) and concentrated under reduced pressure.The residue was purified by HPLC to afford the title compound as apowder (11 mg, 45%). ¹H NMR (400 MHz, (CD₃)₂CO) δ 3.42 (br s, 4H), 3.79(s, 3H), 3.99 (br s, 4H), 4.70 (s, 2H), 5.32 (s, 2H), 6.77 (br s, 1H),6.92 (d, J=8.66 Hz, 2H), 7.44 (d, J=8.53 Hz, 2H), 7.76 (s, 1H), 8.08 (brs, 1H). [M+H]=411.1.

Example 836-(4-Chlorobenzyl)-10,10-dimethyl-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (s, 6H), 2.91 (s, 2H), 4.70 (s, 2H),5.37 (s, 2H), 7.41-7.47 (m, 4H), 8.49 (s, 1H). [M+H]=401.0.

Example 846-Benzyl-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.91 (m, 4H), 2.75 (m, 2H), 3.05 (m, 2H), 5.41(s, 2H), 7.34 (m, 3H), 7.45 (d, 2H), 8.29 (s, 1H). [M+H]=337.0.

Example 856-(3-Chlorobenzyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.83 (m, 4H), 2.68 (m, 2H), 2.93 (m, 2H), 5.28(s, 2H), 7.24 (m, 3H), 7.35 (s, 1H), 8.31 (s, 1H). [M+H]=371.0.

Example 866-([1,1′-Biphenyl]-4-ylmethyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.91 (m, 4H), 2.76 (m, 2H), 3.06 (m, 2H), 5.44(s, 2H), 7.26 (m, 1H), 7.45 (m, 2H), 7.55 (m, 6H), 8.30 (s, 1H).[M+H]=413.0.

Example 876-(4-Chlorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.98-3.01 (m, 2H), 3.93-3.95 (m, 2H), 4.71(s, 2H), 5.38 (s, 2H), 7.40-7.45 (m, 4H), 8.50 (s, 1H). [M+H]=373.0.

Example 886-(4-Methylbenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.26 (s, 3H), 2.98-3.00 (m, 2H), 3.93-3.95(m, 2H), 4.70 (s, 2H), 5.33 (s, 2H), 7.15-7.16 (d, J=4 Hz, 2H),7.27-7.28 (d, J=4 HZ, 2H), 8.50 (s, 1H). [M+H]=353.1.

Example 896-(4-(Trifluoromethyl)benzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.99-3.01 (m, 2H), 3.93-3.96 (m, 2H), 4.70(s, 2H), 5.49 (s, 2H), 7.62-7.64 (d, J=8 Hz, 2H), 7.71-7.73 (d, J=8 Hz,2H), 8.51 (s, 1H). [M+H]=407.1.

Example 906-(4-Methoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.98-3.00 (m, 2H), 3.93-3.95 (m, 2H), 4.71(s, 2H), 5.30 (s, 2H), 6.89-6.91 (d, J=6.9 Hz, 2H), 7.33-7.35 (d, J=6.9Hz, 2H), 8.49 (s, 1H). [M+H]=369.1.

Example 916-(3,4-Dichlorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.99-3.01 (m, 2H), 3.94-3.96 (m, 2H), 4.71(s, 2H), 5.39 (s, 2H), 7.40-7.42 (m, 1H), 7.61-7.62 (m, 1H), 7.76-7.77(m, 1H), 8.49 (s, 1H). [M+H]=408.1.

Example 926-(4-Fluorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.98-3.01 (m, 2H), 3.93-3.95 (m, 2H), 4.71(s, 2H), 5.37 (s, 2H), 7.16-7.20 (m, 2H), 7.45-7.48 (m, 2H), 8.50 (s,1H). [M+H]=357.1.

Example 936-(4-Chloro-3-fluorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.99-3.01 (m, 2H), 3.93-3.96 (m, 2H), 4.70(s, 2H), 5.40 (s, 2H), 7.28-7.30 (m, 1H), 7.53-7.59 (m, 2H), 8.50 (s,1H). [M+H]=391.1.

Example 946-(4-Chloro-2-fluorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.99-3.01 (m, 2H), 3.94-3.96 (m, 2H), 4.71(s, 2H), 5.39 (s, 2H), 7.23-7.25 (m, 1H), 7.40-7.43 (m, 1H), 7.52-7.54(m, 1H), 8.51 (s, 1H). [M+H]=391.1.

Example 956-(3-Fluoro-4-methoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.98-3.00 (m, 2H), 3.80 (s, 3H), 3.93-3.95(m, 2H), 4.71 (s, 2H), 5.31 (s, 2H), 7.11-7.15 (m, 1H), 7.18-7.20 (m,1H), 7.31-7.34 (m, 1H), 8.49 (s, 1H). [M+H]=387.1.

Example 966-(4-(Trifluoromethoxy)benzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.99-3.01 (m, 2H), 3.94-3.96 (m, 2H), 4.71(s, 2H), 5.41 (m, 2H), 7.34-7.36 (d, J=8 Hz, 2H), 7.53-7.55 (d, J=8 Hz,2H), 8.50 (s, 1H). [M+H]=423.1.

Example 976-(4-Ethoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.27-1.30 (t, J=5.6 Hz, 3H), 2.98-3.00 (m,2H), 3.93-4.00 (m, 4H), 4.71 (s, 2H), 5.30 (s, 2H), 6.88-6.90 (d, J=6.8Hz, 2H), 7.32-7.34 (d, J=6.8 Hz, 2H), 8.49 (s, 1H). [M+H]=383.1.

Example 986-(3,5-Difluoro-4-methoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.23 (s, 2H), 3.08-3.10 (m, 2H), 3.94 (s,3H), 4.01-4.03 (m, 2H), 4.85 (s, 2H), 5.67 (s, 2H), 7.39-7.41 (m, 2H),8.61 (s, 1H). [M+H]=405.1.

Example 996-(4-Chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

To a 100 mL flask containing tert-butyl6-(4-chlorobenzyl)-5-oxo-5,6,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9(8H)-carboxylate(0.55 g, 1.17 mmol) was added 4 N hydrogen chloride in dioxane (10 mL).The resulting mixture was stirred at room temperature for four hours andconcentrated under reduced pressure to afford the title compound (0.47g, 99%) as the hydrochloride salt. ¹H NMR (400 MHz, DMSO-d₆) δ 3.20-3.23(m, 2H), 3.42-3.45 (m, 2H), 4.30-4.34 (m, 2H), 5.41 (s, 2H), 7.41-7.45(m, 4H), 8.54 (s, 1H), 9.71 (br. s, 1H). [M+H]=372.1.

Example 100 was made in a manner analogous to Example 99, with theappropriate starting material and reagent substitutions.

Example 1006-(3,4-Dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.84-1.95 (m, 2H), 2.93 (s, 2H), 3.19 (br s,2H), 3.77 (s, 6H), 5.20 (s, 2H), 6.67-6.78 (m, 1H), 6.89-7.00 (m, 2H),8.22-8.30 (m, 1H). [M+H]=398.0.

Example 1016-(4-Chlorobenzyl)-9-methyl-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

To a mixture of6-(4-chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-onehydrochloride (0.045 g, 0.121 mmol) and methyl iodide (0.019 g, 0.133mmol) in DMF (1.5 mL) was added (0.025 g, 0.182 mmol). The resultingmixture was heated to 40° C. After 16 hours the crude mixture was cooledto room temperature, filtered and purified via reverse-phase HPLC toafford the title compound (0.037 g, 81%) as the trifluoroacetic acidsalt. ¹H NMR (400 MHz, DMSO-d₆) δ 2.93-2.99 (m, 2H), 3.18 (s, 3H),3.35-3.37 (m, 2H), 3.74-3.77 (m, 2H), 5.41 (s, 2H), 7.41-7.47 (m, 4H),8.55 (s, 1H). [M+H]=387.1.

Example 1026-(4-Chlorobenzyl)-9-benzyl-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

6-(4-Chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one(80 mg, 0.22 mmol), sodium tri(acetoxy)borohydride (68 mg, 0.32 mmol),benzaldehyde (27 mg, 0.25 mmol) and THF (2 ml) were combined and stirredat room temperature for 18 hours. The mixture was concentrated, dilutedwith methanol, filtered and purified via reverse phase HPLC to affordthe title compound (50 mg, 40%) as the trifluoroacetic acid salt. ¹H NMR(400 MHz, DMSO-d₆) δ 3.16-3.21 (m, 2H), 3.73-3.76 (m, 2H), 4.37-4.39 (m,2H), 4.54 (s, 2H), 5.39 (s, 2H), 7.40-7.43 (m, 4H), 7.49-7.51 (m, 5H),8.54 (s, 1H). [M+H]=462.1.

Examples 103, 105 thru 156 were made in a manner analogous to Example102, with the appropriate starting material and reagent substitutions.

Example 1036-(4-Chlorobenzyl)-9-(cyclopropylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.38-0.42 (m, 2H), 0.66-0.67 (m, 2H),1.07-1.12 (m, 1H), 3.22-3.26 (m, 2H), 3.39-3.45 (m 2H), 3.81-3.85 (m,2H), 4.37-4.39 (m, 1H), 4.73-4.76 (m, 1H), 5.42 (s, 2H), 7.43-7.45 (m,4H), 8.55 (s, 1H). [M+H]=426.2.

Example 104 was made in a manner analogous to Example 82, with theappropriate starting material and reagent substitutions.

Example 1042-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-4-(4-methoxybenzyl)pyrazolo[1,5-c]thieno[3,2-e]pyrimidin-5(4H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.03 (d, J=6.27 Hz, 6H), 1.70 (t, J=10.67Hz, 2H), 2.75 (d, J=10.42 Hz, 2H), 3.51-3.59 (m, 2H), 3.66 (s, 2H), 3.73(s, 3H), 5.29 (s, 2H), 6.84 (d, J=1.76 Hz, 1H), 6.93 (d, J=8.66 Hz, 2H),7.35 (d, J=8.66 Hz, 2H), 7.40 (s, 1H), 8.05-8.14 (m, 1H). [M+H]=439.3.

Example 1056-(4-Chlorobenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.20-1.26 (m, 2H), 1.62-1.66 (m, 2H),2.07-2.11 (m, 1H), 3.14-3.96 (m, 10H), 4.35-4.74 (m, 2H), 5.34-5.51 (m,2H), 7.41-7.46 (m, 4H), 8.56 (s, 1H). [M+H]=470.2.

Example 1066-(4-Chlorobenzyl)-9-(oxetan-3-yl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 3.44-3.48 (m, 4H), 4.34-4.36 (m, 2H),4.40-4.43 (m, 1H), 4.84-4.87 (m, 2H), 5.04-5.07 (m, 2H), 5.36 (s, 2H),7.26-7.33 (d, J=8 Hz, 2H), 7.37-7.39 (d, J=8 Hz, 2H), 8.32 (s, 1H).[M+H]=428.1.

Example 1076-(4-Chlorobenzyl)-9-(2,2,2-trifluoroethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CD3OD) δ 3.09-3.13 (m, 4H), 3.31-3.35 (m, 2H),3.92-3.94 (m, 2H), 5.43 (s, 2H), 7.35-7.37 (d, J=8.0 Hz, 2H), 7.42-7.44(d, J=8.0 Hz, 2H), 8.39 (s, 1H). [M+H]=454.1.

Example 1086-(4-Methoxybenzyl)-9-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.72 (s, 3H), 3.08-3.12 (m, 2H), 3.13-3.17(m, 2H), 3.71-3.74 (m, 5H), 4.39-4.42 (m, 2H), 5.30 (s, 2H), 6.89-6.91(d, J=9.2 Hz, 2H), 7.33-7.35 (d, J=9.2 Hz, 2H), 8.51 (s, 1H).[M+H]=480.2.

Example 1096-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.08-1.20 (m, 2H), 1.62 (d, J=12.30 Hz, 2H),1.82 (ddd, J=10.73, 7.22, 3.89 Hz, 1H), 2.35 (d, J=7.15 Hz, 2H),2.74-2.82 (m, 2H), 2.96 (br s, 2H), 3.29 (t, J=11.29 Hz, 2H), 3.60 (s,2H), 3.73 (s, 3H), 3.82 (dd, J=11.11, 2.82 Hz, 2H), 5.30 (s, 2H), 6.91(d, J=8.53 Hz, 2H), 7.35 (d, J=8.41 Hz, 2H), 8.49 (s, 1H). [M+H]=466.2.

Example 1109-(Cyclopropylmethyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.40-0.41 (m, 2H), 0.66-0.68 (m, 2H),1.08-1.11 (m, 1H) 3.21-3.25 (m, 2H), 3.38-3.38 (m, 2H), 3.72 (s, 3H),3.83-3.86 (m, 2H), 4.37-4.76 (m, 2H), 5.34-5.36 (m, 2H), 6.90-6.92 (d,J=6.8 Hz, 2H), 7.34-7.36 (d, J=6.8 Hz, 2H), 8.55 (s, 1H). [M+H]=422.2.

Example 1116-(4-Methoxybenzyl)-9-((3-methyloxetan-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.63-1.65 (m, 2H), 3.48-3.55 (m, 5H), 3.78 (s,3H), 3.96-3.98 (m, 2H), 4.35 (br. s, 2H), 4.47-4.50 (m, 4H), 5.34 (s,2H), 6.86-6.88 (d, J=6.8 Hz, 2H), 7.37-7.39 (d, J=6.8 Hz, 2H), 8.30 (s,1H). [M+H]=452.2.

Example 1126-(4-Methoxybenzyl)-9-(3-(methylthio)propyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.97-2.02 (m, 2H), 2.07 (s, 3H), 2.53-2.56(m, 2H), 3.24-3.34 (m, 4H), 3.72 (s, 1H), 3.82-3.86 (m, 2H), 4.37-4.39(m, 1H), 4.68-4.71 (m, 1H), 5.34-5.36 (m, 2H), 6.90-6.92 (d, J=6.8 Hz,2H), 7.34-7.36 (d, J=6.8 Hz, 2H), 8.54 (s, 1H). [M+H]=456.1.

Example 1136-(4-Methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.22-1.24 (m, 1H), 1.61-1.63 (m, 1H),2.09-2.11 (m, 1H), 2.63-2.67 (m, 1H), 3.26-3.35 (m, 3H), 3.62-3.67 (m,2H), 3.72 (s, 3H), 3.73-3.78 (m, 2H), 3.83-3.86 (m, 2H), 4.34-4.37 (m,1H), 4.70-4.74 (m, 1H), 6.90-6.92 (d, J=7.2 Hz, 2H), 7.34-7.36 (d, J=7.2Hz, 2H), 8.55 (s, 1H). [M+H]=452.2.

Example 1149-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.17-3.21 (m, 2H), 3.50-3.55 (m, 2H), 3.72(m, 3H), 4.33-4.65 (m, 4H), 5.32 (s, 2H), 6.88-6.90 (d, J=7.2 Hz, 2H),7.32-7.34 (d, J=7.2 Hz, 2H), 7.35-7.37 (m, 1H), 7.52-7.54 (m, 2H), 8.54(s, 1H). [M+H]=538.2.

Example 1156-(4-Methoxybenzyl)-9-neopentyl-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.06 (s, 9H), 3.01-3.03 (m, 2H), 3.23-3.26(m, 2H), 3.54-3.57 (m, 2H), 3.72 (s, 3H), 4.43-4.46 (m, 1H), 4.67-4.70(m, 1H), 5.29-5.41 (m, 2H), 6.90-6.92 (d, J=6.8 Hz, 2H), 7.34-7.36 (d,J=6.8 Hz, 2H), 8.56 (s, 1H). [M+H]=438.1.

Example 1166-(4-Methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.33-3.35 (m, 2H), 3.57-3.59 (m, 2H), 3.72(s, 3H), 4.57-4.60 (m, 2H), 4.76-4.78 (m, 2H), 5.33 (s, 2H), 6.90-6.91(d, J=6.8 Hz, 2H), 7.33-7.35 (d, J=6.8 Hz, 2H), 7.60-7.62 (m, 1H), 8.54(s, 1H), 8.93-8.94 (d, J=3.6 Hz, 1H). [M+H]=460.1.

Example 1176-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.19-1.23 (m, 2H), 1.46-1.57 (m, 4H),1.79-1.82 (m, 1H), 3.28-3.48 (m, 8H), 3.72 (s, 3H), 4.38-4.41 (m, 1H),4.63-4.68 (m, 1H), 5.30-5.35 (m, 2H), 6.91-6.93 (d, J=7.6 Hz, 2H),7.35-7.37 (d, J=7.6, 2H), 8.54 (s, 1H). [M+H]=466.2.

Example 1186-(4-Methoxybenzyl)-9-(3-(methylsulfonyl)propyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.97-2.06 (m, 2H), 2.14-2.18 (m, 2H),3.00-3.02 (m, 2H), 3.02 (s, 3H), 3.15-3.26 (m, 4H), 3.72 (s, 3H),4.36-4.39 (m, 1H), 4.69-4.72 (m, 1H), 5.33-5.35 (m, 2H), 6.90-6.92 (d,J=6.8 Hz, 2H), 7.34-7.36 (d, J=6.8 Hz, 2H), 8.55 (s, 1H). [M+H]=488.2.

Example 1196-(4-Methoxybenzyl)-9-(pyrimidin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.19-3.24 (m, 2H), 3.38-3.42 (m, 2H), 3.72(s, 3H), 4.19-4.45 (m, 4H), 5.32 (s, 2H), 6.90-6.92 (m, 2H), 7.34-7.36(m, 2H), 7.63-7.65 (m, 1H), 8.52 (s, 1H), 8.85-8.87 (m, 1H), 9.25 (s,1H). [M+H]=460.2.

Example 1206-(4-Methoxybenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.25-3.31 (m, 2H), 3.54-3.61 (m, 2H), 3.72(s, 3H), 4.39-4.45 (m, 2H), 4.53 (s, 2H), 5.35 (s, 2H), 6.90-6.92 (m,2H), 7.34-7.36 (m, 2H), 7.47-7.50 (m, 1H), 7.59-7.62 (m, 2H), 7.90-7.94(m, 1H), 8.55 (s, 1H), 8.65-8.69 (m, 1H). [M+H]=459.2.

Example 1216-(4-Methoxybenzyl)-9-(pyridin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.18-3.21 (m, 2H), 3.27-3.32 (m, 2H), 3.72(s, 3H), 4.12-4.17 (m, 2H), 4.31 (s, 2H), 5.35 (s, 2H), 6.90-6.92 (m,2H), 7.34-7.36 (m, 2H), 7.69-7.73 (m, 2H), 8.52 (s, 1H), 8.72-8.78 (m,2H). [M+H]=459.2.

Example 1226-(4-Methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.98-3.03 (m, 2H), 3.08-3.11 (m, 2H), 3.72(s, 3H), 3.78-3.85 (m, 5H), 4.13 (s, 2H), 5.32 (m, 2H), 6.90-6.92 (m,2H), 7.34-7.36 (m, 2H), 7.59 (s, 1H), 7.65 (s, 1H), 8.49 (s, 1H).[M+H]=462.1.

Example 1236-(4-Methoxybenzyl)-9-((4-methylthiazol-5-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.45 (s, 3H), 3.15-3.55 (br. m, 5H), 3.72(s, 3H), 4.05-4.15 (m, 2H), 4.35-4.58 (m, 2H), 5.35 (s, 2H), 6.90-6.92(m, 2H), 7.34-7.36 (m, 2H), 8.55 (s, 1H), 9.08 (s, 1H). [M+H]=479.1.

Example 1249-(1,1-Dioxidothietan-3-yl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.83-2.88 (m, 2H), 3.02-3.06 (m, 2H),3.54-3.57 (m, 1H), 3.71-3.78 (m, 5H), 4.21-4.25 (m, 2H), 4.29-4.36 (m,2H), 5.33 (s, 2H), 6.90-6.92 (m, 2H), 7.34-7.36 (m, 2H), 8.55 (s, 1H).[M+H]=472.2.

Example 1259-((1,4-Dioxan-2-yl)methyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.25-3.35 (m, 2H), 3.49-3.58 (m, 2H),3.68-3.72 (m, 4H), 3.73-3.77 (m, 4H), 3.79-3.83 (m, 2H), 3.98-4.02 (m,2H), 4.39-4.68 (m, 2H), 5.35 (s, 2H), 6.90-6.92 (m, 2H), 7.34-7.36 (m,2H), 8.55 (s, 1H). [M+H]=468.2.

Example 1266-(4-Methoxybenzyl)-9-((5-oxotetrahydrofuran-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.89-1.95 (m, 1H), 2.32-2.39 (m, 2H),3.19-3.28 (m, 2H), 3.42-3.62 (m, 4H), 3.77 (s, 3H), 4.28-4.56 (m, 4H),5.32 (s, 2H), 6.90-6.92 (m, 2H), 7.34-7.36 (m, 2H), 8.55 (s, 1H).[M+H]=466.2.

Example 1279-(4-Fluorobenzyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.74 (s, 3H), 4.15-4.74 (m, 7H), 5.34 (s,2H), 6.88-6.95 (m, 2H), 7.30-7.39 (m, 4H), 7.55-7.64 (m, 2H), 8.56 (s,1H). [M+H]=476.1.

Example 1289-(2-Fluorobenzyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.29 (br s, 2H), 3.74 (s, 3H), 4.21-4.64 (m,6H), 5.34 (s, 2H), 6.87-6.95 (m, 2H), 7.29-7.40 (m, 4H), 7.50-7.67 (m,2H), 8.55 (s, 1H). [M+H]=476.1.

Example 1296-(4-Chloro-2-fluorobenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.26 (qd, J=12.05, 4.14 Hz, 2H), 1.67 (d,J=14.68 Hz, 2H), 2.12 (br s, 1H), 3.33 (br s, 7H), 3.76-3.93 (m, 4H),4.30-4.46 (m, 1H), 4.69-4.85 (m, 1H), 5.35-5.58 (m, 2H), 7.25-7.32 (m,1H), 7.43-7.52 (m, 1H), 7.53-7.61 (m, 1H), 8.58 (s, 1H), 9.87-10.04 (m,1H). [M+H]=488.2.

Example 1306-(4-Chloro-2-fluorobenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.27-3.39 (m, 2H), 3.58-3.73 (m, 2H),4.43-4.52 (m, 2H), 4.56-4.68 (m, 2H), 5.38-5.47 (m, 2H), 7.23-7.30 (m,1H), 7.43-7.49 (m, 1H), 7.50-7.61 (m, 3H), 7.94-8.01 (m, 1H), 8.57 (s,1H), 8.69-8.73 (m, 1H). [M+H]=481.1.

Example 1316-(4-Chloro-2-fluorobenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.93-3.01 (m, 2H), 3.08 (d, J=5.27 Hz, 2H),3.77-3.86 (m, 5H), 4.13 (s, 2H), 5.41 (s, 2H), 7.23-7.30 (m, 1H),7.41-7.48 (m, 1H), 7.52-7.58 (m, 1H), 7.63 (d, J=1.88 Hz, 1H), 7.70 (d,J=1.88 Hz, 1H), 8.53 (s, 1H). [M+H]=484.1.

Example 1326-(4-Chloro-2-fluorobenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.38 (br s, 2H), 3.78 (br s, 2H), 4.63 (brs, 2H), 4.81 (s, 2H), 5.43 (s, 2H), 7.27 (dd, J=8.41, 1.88 Hz, 1H),7.43-7.50 (m, 1H), 7.55 (dd, J=10.16, 2.01 Hz, 1H), 7.60-7.66 (m, 1H),8.57 (s, 1H), 8.96 (d, J=4.89 Hz, 2H). [M+H]=482.1.

Example 1336-(4-Chloro-2-fluorobenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.58-1.74 (m, 1H), 2.07-2.20 (m, 1H),2.61-2.76 (m, 1H), 3.19-3.39 (m, 3H), 3.40-3.56 (m, 2H), 3.67 (d, J=8.28Hz, 2H), 3.73-3.82 (m, 2H), 3.82-3.95 (m, 3H), 4.28-4.51 (m, 2H),4.61-4.87 (m, 2H), 5.37-5.52 (m, 3H), 7.24-7.30 (m, 1H), 7.43-7.52 (m,1H), 7.53-7.60 (m, 1H), 8.58 (s, 1H), 9.96-10.22 (m, 1H). [M+H]=472.1.

Example 1346-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.28-1.42 (m, 1H), 1.44-1.67 (m, 2H),1.80-1.95 (m, 1H), 2.03-2.18 (m, 1H), 3.05-3.54 (m, 7H), 3.74 (s, 4H),3.79-3.90 (m, 2H), 4.24-4.48 (m, 1H), 4.60-4.87 (m, 2H), 5.24-5.49 (m,2H), 6.94 (s, 2H), 7.32-7.42 (m, 2H), 8.56 (s, 1H), 9.89-10.22 (m, 1H).[M+H]=466.2.

Example 13511,11-Difluoro-6-(4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.25-1.39 (m, 2H), 1.69-1.78 (m, 2H),1.80-1.94 (m, 1H), 2.58 (d, J=7.28 Hz, 2H), 3.28 (t, J=11.54 Hz, 2H),3.38-3.47 (m, 2H), 3.82 (s, 5H), 3.96-4.04 (m, 2H), 5.40 (s, 2H), 6.91(d, J=8.66 Hz, 2H), 7.41 (d, J=8.66 Hz, 2H), 8.42 (s, 1H). [M+H]=502.2.

Example 13611,11-Difluoro-6-(4-methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.23-1.38 (m, 1H), 1.60-1.73 (m, 2H),1.85-1.93 (m, 1H), 1.94-2.04 (m, 1H), 2.63 (d, J=7.15 Hz, 2H), 3.21-3.38(m, 3H), 3.44-3.55 (m, 1H), 3.82 (s, 4H), 3.85-3.94 (m, 3H), 3.95-4.02(m, 1H), 5.40 (s, 2H), 6.91 (d, J=8.41 Hz, 2H), 7.41 (d, J=8.41 Hz, 2H),8.45 (s, 1H). [M+H]=502.2.

Example 1376-(2-Fluoro-4-methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.30-3.42 (m, 4H), 3.73-3.81 (m, 5H),4.55-4.66 (m, 2H), 4.75-4.83 (m, 2H), 5.38 (s, 2H), 6.76 (dd, J=8.60,2.45 Hz, 1H), 6.91 (dd, J=12.49, 2.45 Hz, 1H), 7.34 (t, J=8.91 Hz, 1H),7.63 (t, J=4.96 Hz, 1H), 8.57 (s, 1H), 8.96 (d, J=4.89 Hz, 2H).[M+H]=478.1.

Example 1386-(2-Fluoro-4-methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.93-3.00 (m, 2H), 3.04-3.12 (m, 2H),3.75-3.84 (m, 8H), 4.11 (s, 2H), 5.36 (s, 2H), 6.75 (dd, J=8.66, 2.51Hz, 1H), 6.91 (dd, J=12.49, 2.45 Hz, 1H), 7.32 (t, J=8.78 Hz, 1H),7.60-7.71 (m, 2H), 8.53 (s, 1H). [M+H]=480.1.

Example 1396-(2-Fluoro-4-methoxybenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.30-3.36 (m, 2H), 3.64-3.70 (m, 2H), 3.77(s, 3H), 4.49 (br s, 2H), 4.64 (s, 2H), 5.37 (s, 2H), 6.75 (dd, J=8.60,2.45 Hz, 1H), 6.91 (dd, J=12.49, 2.45 Hz, 1H), 7.34 (t, J=8.85 Hz, 1H),7.53 (dd, J=6.84, 5.08 Hz, 1H), 7.59 (d, J=7.78 Hz, 1H), 7.98 (td,J=7.72, 1.76 Hz, 1H), 8.57 (s, 1H), 8.71 (d, J=4.89 Hz, 1H).[M+H]=477.2.

Example 1406-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.59-1.71 (m, 1H), 2.07-2.19 (m, 1H),2.63-2.73 (m, 1H), 3.19-3.47 (m, 7H), 3.63-3.70 (m, 3H), 3.77 (s, 3H),3.82-3.90 (m, 2H), 5.36-5.49 (m, 2H), 6.76 (dd, J=8.60, 2.45 Hz, 1H),6.92 (dd, J=12.49, 2.45 Hz, 1H), 7.35 (t, J=8.91 Hz, 1H), 8.57 (s, 1H).[M+H]=470.2.

Example 1416-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.04-1.24 (m, 2H), 1.55-1.67 (m, 2H),1.75-1.90 (m, 1H), 2.32-2.39 (m, 2H), 2.74-2.83 (m, 2H), 2.91-3.00 (m,2H), 3.24-3.33 (m, 2H), 3.57-3.63 (m, 2H), 3.76 (s, 3H), 3.79-3.87 (m,2H), 5.33 (s, 2H), 6.74 (dd, J=8.60, 2.32 Hz, 1H), 6.90 (dd, J=12.42,2.38 Hz, 1H), 7.30 (t, J=8.85 Hz, 1H), 8.49 (s, 1H). [M+H]=484.2.

Example 1426-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.53-1.81 (m, 3H), 2.03-2.33 (m, 2H),3.11-3.28 (m, 2H), 3.39-3.61 (m, 6H), 3.78-3.87 (m, 5H), 3.95 (d,J=10.29 Hz, 2H), 5.45 (s, 2H), 6.65-6.74 (m, 2H), 7.39 (t, J=8.41 Hz,1H), 8.34 (s, 1H). [M+H]=484.2.

Example 1436-(4-Methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.74-1.86 (m, 2H), 3.06-3.14 (m, 3H),3.71-3.76 (m, 6H), 3.94-4.01 (m, 2H), 4.07-4.14 (m, 2H), 5.31 (s, 2H),6.93 (d, J=8.66 Hz, 2H), 7.37 (d, J=8.66 Hz, 2H), 7.55-7.59 (m, 1H),7.63-7.67 (m, 1H), 8.54 (s, 1H). [M+H]=466.2.

Example 1446-(4-Methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.74-1.86 (m, 2H), 3.06-3.14 (m, 3H),3.71-3.76 (m, 6H), 3.94-4.01 (m, 2H), 4.07-4.14 (m, 2H), 5.31 (s, 2H),6.93 (d, J=8.66 Hz, 2H), 7.37 (d, J=8.66 Hz, 2H), 7.55-7.59 (m, 1H),7.63-7.67 (m, 1H), 8.54 (s, 1H). [M+H]=476.2.

Example 1456-(4-Methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.03-2.17 (m, 2H), 3.49-3.57 (m, 3H),3.63-3.73 (m, 2H), 3.75 (s, 3H), 4.45-4.63 (m, 2H), 4.66-4.81 (m, 2H),5.33 (br s, 2H), 6.94 (d, J=8.53 Hz, 2H), 7.38 (d, J=8.53 Hz, 2H), 7.60(t, J=4.96 Hz, 1H), 8.57 (s, 1H), 8.90 (d, J=5.02 Hz, 1H). [M+H]=474.2.

Example 1466-(4-Methoxybenzyl)-9-(pyridin-2-ylmethyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.02-2.15 (m, 2H), 3.57-3.68 (m, 4H), 3.76(s, 3H), 4.40-4.49 (m, 2H), 4.66-4.75 (m, 2H), 5.34 (s, 2H), 6.95 (d,J=8.53 Hz, 2H), 7.38 (d, J=8.53 Hz, 2H), 7.46 (d, J=7.78 Hz, 1H),7.48-7.54 (m, 1H), 7.87-7.94 (m, 1H), 8.58 (s, 1H), 8.68 (d, J=4.52 Hz,1H). [M+H]=473.2.

Example 1476-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.07-1.26 (m, 2H), 1.39-1.52 (m, 1H),1.61-1.73 (m, 1H), 1.90-2.20 (m, 3H), 2.92 (br s, 3H), 3.21-3.36 (m,3H), 3.64-3.72 (m, 2H), 3.74 (s, 3H), 3.79-3.88 (m, 2H), 4.63-4.86 (m,2H), 5.36 (d, J=7.78 Hz, 2H), 6.93 (d, J=8.66 Hz, 2H), 7.38 (d, J=8.66Hz, 2H), 8.57 (s, 1H). [M+H]=480.3.

Example 1486-(4-Methoxybenzyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.13-1.27 (m, 2H), 1.51-1.62 (m, 2H),1.84-1.99 (m, 3H), 2.89 (t, J=6.21 Hz, 2H), 2.95 (d, J=7.03 Hz, 2H),3.17-3.32 (m, 4H), 3.74 (s, 3H), 3.81-3.90 (m, 2H), 5.25 (s, 2H), 6.92(d, J=8.66 Hz, 2H), 7.34 (d, J=8.66 Hz, 2H), 8.45 (s, 1H). [M+H]=466.2.

Example 1496-(4-Methoxybenzyl)-8-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.18-1.33 (m, 1H), 1.40-1.54 (m, 1H),1.54-1.64 (m, 1H), 1.71-1.82 (m, 1H), 1.87-1.99 (m, 3H), 2.85-2.97 (m,4H), 3.16-3.23 (m, 2H), 3.68-3.79 (m, 7H), 5.26 (s, 2H), 6.93 (d, J=8.66Hz, 2H), 7.34 (d, J=8.66 Hz, 2H), 8.45 (s, 1H). [M+H]=466.2.

Example 1506-(4-Methoxybenzyl)-8-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.50-1.61 (m, 1H), 1.90-1.99 (m, 2H),2.86-2.93 (m, 2H), 3.01-3.07 (m, 2H), 3.17-3.25 (m, 2H), 3.39-3.44 (m,2H), 3.69-3.79 (m, 7H), 5.26 (s, 2H), 6.92 (d, J=8.78 Hz, 2H), 7.34 (d,J=8.66 Hz, 2H), 8.46 (s, 1H). [M+H]=452.2.

Example 1519-(1,1-Difluoropropan-2-yl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CD₃OD) δ 1.47 (d, J=6.90 Hz, 3H), 3.35-3.40 (m, 2H),3.55-3.62 (m, 2H), 3.75-3.86 (m, 5H), 4.38-4.45 (m, 2H), 5.42 (s, 2H),6.93 (d, J=8.66 Hz, 2H), 7.42 (d, J=8.66 Hz, 2H), 8.44 (s, 1H).[M+H]=446.2.

Example 1528-(4-Chlorobenzyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.89-2.01 (m, 3H), 2.92 (t, J=6.27 Hz, 2H),3.03-3.15 (m, 2H), 3.71 (s, 3H), 4.13 (s, 2H), 5.16 (s, 2H), 6.69-6.82(m, 2H), 7.13-7.32 (m, 8H), 8.14-8.25 (m, 1H). [M+H]=492.0.

Example 1538-(4-Chlorobenzyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.95 (br s, 2H), 2.93 (s, 2H), 3.10 (br s,2H), 3.76 (d, J=18.57 Hz, 7H), 4.14 (s, 2H), 5.15 (s, 2H), 6.68-6.76 (m,1H), 6.81-6.87 (m, 1H), 6.89-6.96 (m, 1H), 7.19-7.32 (m, 4H), 8.18-8.25(m, 1H). [M+H]=523.0.

Example 1548-Benzyl-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.87-2.01 (m, 2H), 2.91 (t, J=6.27 Hz, 2H),3.11 (br s, 2H), 3.71-3.81 (m, 7H), 4.20 (s, 2H), 5.17 (s, 2H),6.69-6.76 (m, 1H), 6.84-6.95 (m, 2H), 7.27 (d, J=5.02 Hz, 5H), 8.24-8.30(m, 1H). [M+H]=488.0.

Example 1558-(3-Chlorobenzyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.89-2.01 (m, 2H), 2.92 (s, 2H), 3.12 (br s,2H), 3.76 (d, J=16.31 Hz, 6H), 4.16 (s, 2H), 5.17 (s, 2H), 6.68-6.75 (m,1H), 6.84-6.94 (m, 2H), 7.18 (m, 3H), 8.23-8.29 (m, 1H). [M+H]=523.0.

Example 15611,11-Difluoro-6-(2-fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.06-1.22 (m, 2H), 1.55-1.66 (m, 2H),1.78-1.94 (m, 1H), 2.44-2.49 (m, 2H), 3.21 (t, J=11.86 Hz, 2H), 3.30 (t,J=11.04 Hz, 2H), 3.77 (s, 3H), 3.79-3.87 (m, 4H), 5.39 (s, 2H), 6.75(dd, J=8.66, 2.51 Hz, 1H), 6.92 (dd, J=12.55, 2.38 Hz, 1H), 7.36 (t,J=8.85 Hz, 1H), 8.53 (s, 1H). [M+H]=520.2.

Example 1576-(4-Chlorobenzyl)-9-(pyrazine-2-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

6-(4-Chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one(80 mg, 0.22 mmol), pyrazinecarboxylic acid (29 mg, 0.24 mmol), HATU (82mg, 0.22 mmol) and triethylamine (0.090 mL, 0.65 mmol) were combined inDMF (2 mL) and stirred at room temperature for 18 hours. The mixture wasfiltered and purified by reverse phase HPLC to afford the title compound(61 mg, 47%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.10-3.14 (m, 2H), 3.74-3.76(m, 2H), 4.01-4.04 (m, 2H), 5.40 (s, 2H), 7.41-7.46 (m, 4H), 8.54 (s,1H), 8.73-8.76 (m, 1H), 8.80 (m, 1H), 8.85-8.90 (m, 1H). [M+H]=478.1.

Examples 158 thru 178 were made in a manner analogous to Example 157,with the appropriate starting material and reagent substitutions.

Example 1586-(4-Chlorobenzyl)-9-(cyclopropanecarbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.73-0.76 (m, 4H), 2.03-2.10 (m, 1H),3.01-3.06 (m, 2H), 3.89-3.96 (m, 2H), 4.76-4.87 (m, 2H), 5.37 (s, 1H),7.41-7.44 (m, 4H), 8.50 (s, 1H). [M+H]=440.1.

Example 1599-(Cyclopropanecarbonyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.74-0.75 (m, 4H), 1.95-1.98 (minor)2.12-2.15 (major) (m, 1H), 2.94-2.96 (minor) 3.08-3.10 (major) (m, 2H),3.79-3.81 (minor) 4.02-4.04 (major) (m, 2H), 4.66-4.68 (major) 4.95-4.97(major) (m, 2H), 5.30 (s, 2H), 6.90-6.91 (d, J=6.8 Hz, 2H), 7.33-7.35(d, J=6.8 Hz, 2H), 8.49 (s, 1H). [M+H]=436.2.

Example 1609-(2,2-Difluorocyclopropanecarbonyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.86-1.96 (m, 2H), 2.97-3.05 (m, 2H),3.31-3.34 (m, 1H), 3.72 (s, 3H), 3.82-4.00 (m, 2H), 4.69-4.82 (m, 2H),5.30 (s, 2H), 6.89-6.91 (m, 2H), 7.33-7.35 (m, 2H), 8.50 (s, 1H).[M+H]=472.2.

Example 1616-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.89-2.18 (m, 2H), 2.92-3.14 (m, 2H),3.46-3.59 (m, 1H), 3.63-3.78 (m, 6H), 3.80-3.99 (m, 3H), 4.64-4.87 (m,2H), 5.32 (s, 2H), 6.88-6.97 (m, 2H), 7.36 (d, J=8.41 Hz, 2H), 8.51 (s,1H). [M+H]=466.1

Example 1626-(4-Methoxybenzyl)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.96 (s, 3H), 3.09-3.12 (m, 2H), 3.54-3.57(m, 2H), 3.72 (s, 2H), 4.46 (s, 2H), 5.31 (s, 2H), 6.90-6.92 (d, J=7.2Hz, 2H), 7.34-7.35 (d, J=7.2 Hz, 2H), 8.50 (s, 1H). [M+H]=446.1.

Example 1636-(4-Methoxybenzyl)-9-(1-methylpyrrolidine-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.75-2.25 (m, 2H), 2.85-2.92 (m, 3H),3.02-3.18 (m, 4H) 3.20-3.38 (m, 1H), 3.52-3.61 (m, 2H), 3.72 (s, 3H),3.81-3.90 (m, 2H), 4.65-4.85 (m, 2H), 5.29-5.35 (m, 2H), 6.90-6.92 (m,2H), 7.34-7.36 (m, 2H), 8.55 (s, 1H). [M+H]=479.2.

Example 1646-(4-Chloro-2-fluorobenzyl)-9-(cyclopropanecarbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.77 (d, J=5.52 Hz, 4H), 1.91-2.24 (m, 1H),2.88-3.19 (m, 2H), 3.51-3.91 (m, 6H), 3.98-4.13 (m, 1H), 4.63-4.77 (m,1H), 4.92-5.05 (m, 1H), 5.37-5.46 (m, 2H), 7.21-7.32 (m, 1H), 7.38-7.50(m, 1H), 7.51-7.62 (m, 1H), 8.53 (s, 1H). [M+H]=458.1.

Example 1656-(4-Chloro-2-fluorobenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.90-2.18 (m, 2H), 2.95-3.03 (m, 1H),3.06-3.13 (m, 1H), 3.34-3.57 (m, 2H), 3.72 (br s, 8H), 3.81-3.99 (m,3H), 4.71 (d, J=4.89 Hz, 1H), 4.82 (br s, 1H), 5.38-5.44 (m, 2H), 5.77(s, 1H), 7.23-7.30 (m, 1H), 7.40-7.49 (m, 1H), 7.51-7.61 (m, 1H),8.48-8.56 (m, 1H). [M+H]=502.1.

Example 16611,11-Difluoro-6-(4-methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.89-2.18 (m, 2H), 3.53-3.63 (m, 1H),3.65-3.73 (m, 2H), 3.75 (s, 3H), 3.84-3.98 (m, 1H), 4.21-4.34 (m, 1H),4.41 (t, J=11.23 Hz, 1H), 4.86 (br s, 1H), 4.99 (br s, 1H), 5.38 (d,J=6.78 Hz, 2H), 5.77 (s, 1H), 6.94 (dd, J=8.72, 3.33 Hz, 2H), 7.34-7.47(m, 2H), 8.48-8.58 (m, 1H). [M+H]=502.1.

Example 1676-(2-Fluoro-4-methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.91-2.17 (m, 2H), 2.94-3.02 (m, 1H),3.05-3.12 (m, 1H), 3.47-3.56 (m, 1H), 3.65-3.75 (m, 3H), 3.77 (s, 3H),3.81-3.97 (m, 3H), 4.68-4.85 (m, 2H), 5.36 (br s, 2H), 6.75 (dd, J=8.53,2.51 Hz, 1H), 6.91 (dd, J=12.55, 2.51 Hz, 1H), 7.31 (t, J=9.03 Hz, 1H),8.52 (s, 1H). [M+H]=484.1.

Example 1689-(Cyclopropanecarbonyl)-6-(2-fluoro-4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.77 (d, J=5.40 Hz, 4H), 1.96-2.21 (m, 1H),3.07-3.16 (m, 2H), 3.77 (s, 3H), 3.80-4.09 (m, 2H), 4.66-5.03 (m, 2H),5.36 (s, 2H), 6.75 (d, J=8.16 Hz, 1H), 6.91 (d, J=12.30 Hz, 1H),7.27-7.37 (m, 1H), 8.52 (s, 1H). [M+H]=454.1.

Example 169(R)-6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.91-2.18 (m, 2H), 2.94-3.12 (m, 3H),3.65-3.77 (m, 6H), 3.81-3.98 (m, 3H), 4.68-4.84 (m, 2H), 5.32 (s, 2H),6.90-6.97 (m, 2H), 7.36 (d, J=8.66 Hz, 2H), 8.52 (s, 1H). [M+H]=466.1.

Example 1706-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.89-2.18 (m, 2H), 2.92-3.14 (m, 2H),3.46-3.59 (m, 1H), 3.63-3.78 (m, 6H), 3.80-3.99 (m, 3H), 4.64-4.87 (m,2H), 5.32 (s, 2H), 6.88-6.97 (m, 2H), 7.36 (d, J=8.41 Hz, 2H), 8.51 (s,1H). [M+H]=466.1.

Example 1716-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.89-2.18 (m, 2H), 2.92-3.14 (m, 2H),3.46-3.59 (m, 1H), 3.63-3.78 (m, 6H), 3.80-3.99 (m, 3H), 4.64-4.87 (m,2H), 5.32 (s, 2H), 6.88-6.97 (m, 2H), 7.36 (d, J=8.41 Hz, 2H), 8.51 (s,1H). [M+H]=466.1.

Example 172(R)-6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.73-2.10 (m, 4H), 3.42 (br s, 3H),3.57-3.70 (m, 3H), 3.71-3.93 (m, 6H), 4.58-4.65 (m, 1H), 4.80-4.86 (m,1H), 5.29 (s, 2H), 6.93 (d, J=8.28 Hz, 2H), 7.33-7.42 (m, 2H), 8.50 (s,1H). [M+H]=481.2.

Example 1739-(Cyclopropanecarbonyl)-6-(4-methoxybenzyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.56-0.73 (m, 4H), 1.74-1.86 (m, 1H),1.90-2.06 (m, 2H), 3.38-3.43 (m, 2H), 3.74 (s, 3H), 3.77-3.84 (m, 1H),3.99-4.09 (m, 1H), 4.57-4.66 (m, 1H), 4.90-4.98 (m, 1H), 5.25-5.35 (m,2H), 6.93 (d, J=8.28 Hz, 2H), 7.38 (d, J=8.28 Hz, 2H), 8.50 (s, 1H).[M+H]=451.2.

Example 1748-(Cyclopropanecarbonyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.88-0.97 (m, 4H), 2.06-2.29 (m, 3H),3.04-3.12 (m, 2H), 3.73 (s, 3H), 4.13-4.24 (m, 2H), 5.32 (s, 2H), 6.92(d, J=8.66 Hz, 2H), 7.32 (d, J=8.66 Hz, 2H), 8.51 (s, 1H). [M+H]=436.2.

Example 1756-(4-Methoxybenzyl)-8-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.01-2.22 (m, 4H), 3.07 (t, J=6.09 Hz, 2H),3.61-3.86 (m, 7H), 3.90-4.08 (m, 3H), 5.34 (s, 2H), 6.93 (d, J=8.66 Hz,2H), 7.34 (d, J=8.66 Hz, 2H), 8.51 (s, 1H). [M+H]=466.2.

Example 1768-Benzoyl-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.98-2.11 (m, 2H), 3.11 (s, 2H), 3.78 (d,J=9.79 Hz, 6H), 3.86 (br s, 2H), 5.33 (s, 2H), 6.70-6.79 (m, 1H),7.05-7.12 (m, 2H), 7.43 (s, 5H), 8.25-8.32 (m, 1H). [M+H]=502.0.

Example 1778-(3-Chlorobenzoyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 2.06 (d, J=5.77 Hz, 2H), 3.13 (s, 2H),3.72-3.83 (m, 8H), 5.32 (s, 2H), 6.75 (s, 2H), 7.07 (s, 1H), 7.27-7.33(m, 1H), 7.33-7.41 (m, 1H), 7.42 (s, 2H), 8.21-8.28 (m, 1H).[M+H]=537.0.

Example 1788-(4-Chlorobenzoyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.98-2.11 (m, 2H), 3.09-3.17 (m, 2H), 3.77 (d,J=9.29 Hz, 8H), 5.32 (s, 2H), 6.70-6.77 (m, 1H), 7.04-7.11 (m, 2H),7.34-7.45 (m, 4H), 8.24-8.31 (m, 1H). [M+H]=537.0.

Example 1796-(4-Methoxybenzyl)-9-(pyridin-2-yl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one(50 mg, 0.14 mmol), 2-fluoropyridine (40 mg, 0.41 mmol) were combinedDMF (2 mL) and heated at 160° C. by microwave for 1 h. The mixture wasfiltered and purified by reverse phase HPLC to afford the title compound(30 mg, 39%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.08-3.11 (m, 2H), 3.72 (s,3H), 3.97-4.00 (m, 2H), 4.83 s, 2H), 5.31 (s, 2H), 6.74-6.76 (m, 1H),6.90-6.91 (d, J=5.2 Hz, 2H), 7.12-7.13 (m, 1H), 7.34-7.36 (d, J=5.2 Hz,2H), 7.69-7.72 (m, 1H), 8.10-8.11 (m, 1H), 8.49 (s, 8.49). [M+H]=445.1.

Example 1806-(4-Methoxybenzyl)-9-(morpholin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

tert-Butyl2-((6-(4-methoxybenzyl)-5-oxo-5,6,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-9(8H)-yl)methyl)morpholine-4-carboxylate(prepared according to Example 13, 75 mg, 0.13 mmol) was dissolved in 4M hydrogen chloride in dioxane (5 ml). The resulting mixture was stirredat room temperature for 4 hours. The crude mixture was concentrated,taken up methanol, filtered and purified by reverse-phase HPLC. Theproduct was dissolved in methanol (1 mL) and passed through an ionexchange resin cartridge while washing with 10% methanolic ammoniasolution. The collected solution was concentrated under reduced pressureto afford the title compound (33 mg, 53%). ¹H NMR (500 MHz, DMSO-d6) δ2.56-2.76 (m, 4H), 2.81-2.93 (m, 4H), 2.93-3.00 (m, 2H), 3.11-3.15 (m,2H), 3.72 (s, 3H), 3.80-3.93 (m, 3H), 5.30 (s, 2H), 6.91 (d, J=8.30 Hz,2H), 7.34 (d, J=8.82 Hz, 3H), 8.49 (s, 1H). [M+H]=467.2.

Examples 181 thru 182 were made in a manner analogous to Example 180,with the appropriate starting material and reagent substitutions.

Example 1816-(4-Methoxybenzyl)-9-(pyrrolidine-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.80-2.02 (m, 1H), 2.15-2.37 (m, 1H), 2.69(d, J=1.88 Hz, 1H), 3.01 (br s, 1H), 3.09-3.26 (m, 4H), 3.27-3.50 (m,3H), 3.52-3.96 (m, 16H), 4.65-4.78 (m, 1H), 4.79-4.89 (m, 1H), 5.33 (s,1H), 6.89-6.98 (m, 2H), 7.33-7.42 (m, 2H), 8.51-8.56 (m, 1H), 8.68-8.91(m, 2H). [M+H]=465.1.

Example 1826-(4-Methoxybenzyl)-9-(piperidin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.28-1.47 (m, 2H), 1.86-2.00 (m, 2H),2.05-2.23 (m, 1H), 2.79-2.94 (m, 3H), 3.18 (br s, 3H), 3.24-3.37 (m,5H), 3.40-3.59 (m, 2H), 3.75 (s, 4H), 4.25-4.52 (m, 2H), 4.57-4.87 (m,1H), 5.36 (br s, 2H), 6.88-6.98 (m, 2H), 7.31-7.42 (m, 2H), 8.32-8.49(m, 1H), 8.52-8.59 (m, 1H), 8.60-8.72 (m, 1H). [M+H]=465.2.

Examples 183 and 184 were made in a manner analogous to Example 99, withthe appropriate starting material and reagent substitutions.

Example 1836-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.24 (s, 2H), 3.51 (br s, 2H), 3.75 (s, 3H)4.39 (br s, 2H), 5.36 (s, 2H), 6.94 (s, 2H), 7.32-7.42 (m, 2H), 8.53 (s,1H), 9.22-9.29 (m, 1H). [M+H]=368.1.

Example 1846-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,4′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 3.02 (br s, 2H), 3.35 (br s, 2H), 3.79 (s,3H), 4.24 (br s, 2H), 5.21-5.36 (m, 2H), 6.86 (d, J=8.66 Hz, 2H), 7.40(d, J=8.66 Hz, 2H), 8.32 (s, 1H). [M+H]=368.1.

Examples 185 through 215 were made in a manner analogous to Example 43,with the appropriate starting material and reagent substitutions.

Example 1856-(4-Methoxybenzyl)-8-((4-(pyridin-4-yloxy)piperidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.84-2.32 (m, 4H), 3.18 (s, 4H), 3.75 (s,3H), 4.54-4.73 (m, 2H), 4.98-5.17 (m, 1H), 5.36 (s, 2H), 6.95 (d, J=8.53Hz, 2H), 7.41 (d, J=8.53 Hz, 2H), 7.56 (d, J=5.90 Hz, 2H), 7.82 (s, 1H),8.56 (s, 1H), 8.76 (d, J=6.65 Hz, 2H). [M+H]=503.2.

Example 1868-((4-(2-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.89-3.34 (m, 4H), 3.75 (s, 7H), 4.46-4.91(m, 2H), 5.37 (s, 2H), 6.95 (d, J=8.66 Hz, 2H), 6.99-7.24 (m, 4H), 7.41(d, J=8.66 Hz, 2H), 7.66-7.93 (m, 1H), 8.55 (s, 1H). [M+H]=505.2.

Example 1878-((4-(3-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.82-3.45 (m, 4H), 3.75 (s, 3H), 3.78-4.28(m, 4H), 4.39-4.77 (m, 2H), 5.36 (s, 2H), 6.59-6.69 (m, 1H), 6.77-6.87(m, 2H), 6.95 (d, J=8.66 Hz, 2H), 7.27 (q, J=8.03 Hz, 1H), 7.41 (d,J=8.66 Hz, 2H), 7.70-7.86 (m, 1H), 8.55 (s, 1H). [M+H]=505.2.

Example 1888-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.74-3.33 (m, 4H), 3.73-3.82 (m, 5H),3.83-4.23 (m, 2H), 4.41-4.89 (m, 2H), 5.36 (s, 2H), 6.95 (d, J=8.41 Hz,2H), 6.98-7.04 (m, 2H), 7.06-7.15 (m, 2H), 7.41 (d, J=8.53 Hz, 2H),7.60-7.96 (m, 1H), 8.55 (s, 1H). [M+H]=505.2.

Example 1896-(4-Methoxybenzyl)-9-((3-phenoxypyrrolidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.30-3.71 (m, 6H), 3.75 (s, 3H), 4.76-4.99(m, 2H), 5.06-5.25 (m, 1H), 5.36-5.43 (m, 2H), 6.87-7.04 (m, 5H),7.25-7.37 (m, 2H), 7.41 (d, J=8.53 Hz, 2H), 7.70-7.81 (m, 1H), 8.53-8.69(m, 1H). [M+H]=488.2.

Example 1908-((3-(2-Fluorophenoxy)azetidin-1-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.75 (s, 3H), 4.10-4.37 (m, 2H), 4.40-4.77(m, 4H), 5.01-5.17 (m, 1H), 5.35 (s, 2H), 6.94 (d, J=8.66 Hz, 2H),6.97-7.09 (m, 2H), 7.11-7.19 (m, 1H), 7.29 (dd, J=11.54, 8.28 Hz, 1H),7.40 (d, J=8.53 Hz, 2H), 7.80-7.93 (m, 1H), 8.54 (s, 1H). [M+H]=492.1.

Example 1916-(4-Methoxybenzyl)-8-((4-morpholinopiperidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.68-1.91 (m, 2H), 2.16-2.32 (m, 2H),3.26-3.57 (m, 5H), 3.75 (s, 3H), 3.98 (s, 2H), 4.11-4.75 (m, 8H), 5.35(s, 2H), 6.94 (d, J=8.66 Hz, 2H), 7.40 (d, J=8.53 Hz, 2H), 7.66-7.84 (m,1H), 8.55 (s, 1H). [M+H]=495.2.

Example 1928-((1,1-Difluoro-5-azaspiro[2.4]heptan-5-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.55-1.86 (m, 2H), 1.96-2.30 (m, 2H),2.83-3.63 (m, 4H), 3.75 (s, 3H), 4.49-4.86 (m, 2H), 5.36 (s, 2H), 6.95(d, J=8.53 Hz, 2H), 7.41 (d, J=8.53 Hz, 2H), 7.80 (br s, 1H), 8.55 (s,1H). [M+H]=458.1.

Example 1938-((4-Acetyl-1,4-diazepan-1-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.68-2.26 (m, 5H), 2.72-3.70 (m, 8H), 3.75(s, 3H), 4.51-4.80 (m, 2H), 5.36 (s, 2H), 6.94 (d, J=8.53 Hz, 2H), 7.41(d, J=8.41 Hz, 2H), 7.81 (br s, 1H), 8.55 (s, 1H). [M+H]=467.2.

Example 1948-((1,4-Oxazepan-4-yl)methyl)-6-(2,3-difluoro-4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 7.85 (br s, 1H), 7.21-7.30 (m,1H), 6.96-7.05 (m, 1H), 5.42 (s, 2H), 4.61-4.77 (m, 2H), 3.86 (s, 7H),3.33-3.62 (m, 4H), 3.20-3.32 (m, 2H). [M+H]=461.9.

Example 1959-((3-(Hydroxymethyl)-3-isobutylpiperidin-1-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.80-0.94 (m, 6H), 1.02-1.18 (m, 1H),1.29-1.54 (m, 2H), 1.60-1.77 (m, 3H), 1.81-1.97 (m, 1H), 2.81-3.05 (m,2H), 3.20-3.54 (m, 6H), 3.75 (s, 3H), 4.57-4.86 (m, 2H), 5.30-5.51 (m,2H), 6.95 (d, J=8.53 Hz, 2H), 7.43 (d, J=8.41 Hz, 2H), 7.68-7.77 (m,1H), 8.56-8.67 (m, 1H). [M+H]=496.2.

Example 1968-(((2,2-Dimethyltetrahydro-2H-pyran-4-yl)(ethyl)amino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.03-1.30 (m, 9H), 1.46-1.77 (m, 2H),1.83-2.06 (m, 2H), 3.01-3.33 (m, 2H), 3.48-3.69 (m, 2H), 3.72-3.81 (m,4H), 4.57-4.80 (m, 2H), 5.28-5.44 (m, 2H), 6.94 (d, J=8.53 Hz, 2H), 7.40(d, J=8.53 Hz, 2H), 7.90 (br s, 1H), 8.56 (s, 1H). [M+H]=482.2.

Example 1979-((Ethyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.16-1.31 (m, 5H), 1.58-1.80 (m, 2H),2.14-2.29 (m, 1H), 3.03-3.40 (m, 6H), 3.75 (s, 3H), 3.82-3.91 (m, 2H),4.62-4.75 (m, 1H), 4.79-4.91 (m, 1H), 5.30-5.50 (m, 2H), 6.95 (d, J=8.66Hz, 2H), 7.42 (d, J=8.53 Hz, 2H), 7.78 (s, 1H), 8.67 (s, 1H).[M+H]=468.2.

Example 1988-((Ethyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.97-1.35 (m, 5H), 1.46-1.74 (m, 2H),1.84-2.06 (m, 1H), 2.81-3.07 (m, 2H), 3.09-3.33 (m, 4H), 3.74 (s, 3H),3.77-3.86 (m, 2H), 4.66 (br s, 2H), 5.30-5.48 (m, 2H), 6.93 (d, J=8.53Hz, 2H), 7.40 (d, J=8.41 Hz, 2H), 7.89 (s, 1H), 8.56 (s, 1H).[M+H]=468.2.

Example 1996-(4-Methoxybenzyl)-9-((methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.16-1.33 (m, 2H), 1.64-1.77 (m, 2H),2.13-2.31 (m, 1H), 2.78 (br s, 3H), 3.05-3.42 (m, 4H), 3.75 (s, 3H),3.83-3.93 (m, 2H), 4.53-4.67 (m, 2H), 5.30-5.51 (m, 2H), 6.95 (d, J=8.53Hz, 2H), 7.42 (d, J=8.53 Hz, 2H), 7.77 (s, 1H), 8.65 (s, 1H).[M+H]=454.2.

Example 2006-(2,3-Difluoro-4-methoxybenzyl)-8-(((2R,6S)-2,6-dimethylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 7.67 (s, 1H), 7.14-7.22 (m, 1H),6.70-6.79 (m, 1H), 5.44 (s, 2H), 4.41 (s, 2H), 3.97-4.09 (m, 2H), 3.90(s, 3H), 3.76-3.87 (m, 1H), 3.44 (d, J=11.42 Hz, 2H), 2.42 (t, J=11.29Hz, 2H), 1.24 (d, J=6.27 Hz, 6H). [M+H]=476.0.

Example 2018-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(3-fluoro-4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 7.67 (s, 1H), 7.20-7.27 (m, 2H),6.95 (t, J=8.53 Hz, 1H), 5.33 (s, 2H), 4.43 (s, 2H), 3.98-4.11 (m, 2H),3.88 (s, 3H), 3.46 (d, J=11.42 Hz, 2H), 2.45 (t, J=11.17 Hz, 2H), 1.25(d, J=6.27 Hz, 6H). [M+H]=457.9.

Example 2028-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(2-fluoro-4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 8.34 (s, 1H), 7.70 (s, 1H), 7.41 (t, J=8.60Hz, 1H), 6.61-6.73 (m, 2H), 5.45 (s, 2H), 4.41 (s, 2H), 4.04-4.16 (m,2H), 3.80 (s, 3H), 3.43 (d, J=11.29 Hz, 2H), 2.43 (t, J=11.17 Hz, 2H),1.25 (d, J=6.27 Hz, 6H). [M+H]=458.9.

Example 2036-(4-Methoxybenzyl)-9-((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.02-1.19 (m, 2H), 1.54-1.68 (m, 3H),2.37-2.43 (m, 2H), 3.25 (t, J=11.11 Hz, 2H), 3.74 (s, 3H), 3.81 (dd,J=11.23, 3.58 Hz, 2H), 4.01 (s, 2H), 5.34 (s, 2H), 6.93 (d, J=8.53 Hz,2H), 7.25 (s, 1H), 7.39 (d, J=8.53 Hz, 2H), 8.53 (s, 1H). [M+H]=440.2.

Example 2046-(4-Methoxybenzyl)-8-((methyl(tetrahydro-2H-pyran-4-yl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.60-2.06 (m, 4H), 2.61-2.76 (m, 3H), 3.31(t, J=11.73 Hz, 2H), 3.42-3.59 (m, 1H), 3.75 (s, 3H), 3.96-4.05 (m, 2H),4.48-4.81 (m, 2H), 5.37 (s, 2H), 6.94 (d, J=8.66 Hz, 2H), 7.41 (d,J=8.53 Hz, 2H), 7.88 (br s, 1H), 8.56 (s, 1H). [M+H]=440.2.

Example 2056-(3-Chloro-4-fluorobenzyl)-8-(((2R,6S)-2,6-dimethylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 7.67 (s, 1H), 7.57 (dd, J=6.78,2.26 Hz, 1H), 7.35-7.44 (m, 1H), 7.16 (t, J=8.60 Hz, 1H), 5.34 (s, 2H),4.42 (s, 2H), 3.97-4.10 (m, 2H), 3.45 (d, J=11.42 Hz, 2H), 2.43 (t,J=11.23 Hz, 2H), 1.25 (d, J=6.27 Hz, 6H). [M+H]=461.9.

Example 2068-((1,1-Dioxidothiomorpholino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 2.96-3.04 (m, 4H), 3.10-3.17 (m, 4H), 3.74(s, 3H), 3.99 (s, 2H), 5.33 (s, 2H), 6.93 (d, J=8.53 Hz, 2H), 7.40 (d,J=8.41 Hz, 2H), 7.51 (s, 1H), 8.49 (s, 1H). [M+H]=460.1.

Example 2076-(3-Fluoro-4-methoxybenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 7.62 (s, 1H), 7.21-7.27 (m, 2H),6.95 (t, J=8.53 Hz, 1H), 5.33 (s, 2H), 4.33 (s, 2H), 3.97 (br s, 4H),3.89 (s, 3H), 2.97-3.25 (m, 4H). [M+H]=429.9.

Example 2086-(2-Fluoro-4-methoxybenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 1H), 7.66-7.86 (m, 1H), 7.38 (t,J=8.91 Hz, 1H), 6.92 (dd, J=12.49, 2.45 Hz, 1H), 6.77 (dd, J=8.60, 2.45Hz, 1H), 5.37 (s, 2H), 4.47-4.78 (m, 2H), 3.87-4.11 (m, 2H), 3.76 (s,5H), 2.88-3.17 (m, 4H). [M+H]=429.9.

Example 2096-(3-Chloro-4-fluorobenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 7.69 (s, 1H), 7.56 (dd, J=6.78,2.13 Hz, 1H), 7.35-7.44 (m, 1H), 7.16 (t, J=8.53 Hz, 1H), 5.35 (s, 2H),4.44 (s, 2H), 3.95-4.06 (m, 4H), 2.88-3.56 (m, 4H). [M+H]=433.8.

Example 2106-(2,3-Difluoro-4-methoxybenzyl)-8-((methyl((3-methyloxetan-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1H), 7.76 (s, 1H), 7.16-7.27 (m, 1H),6.68-6.82 (m, 1H), 5.47 (s, 2H), 4.42-4.55 (m, 6H), 3.91 (s, 3H),3.37-3.44 (m, 2H), 2.72-2.77 (m, 3H), 1.60 (s, 3H). [M+H]=475.9.

Example 2116-(4-Methoxybenzyl)-8-((((3-methyloxetan-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.28-1.36 (m, 3H), 3.22-3.31 (m, 2H), 3.75(s, 3H), 4.19-4.59 (m, 6H), 5.37 (s, 2H), 6.94 (d, J=8.53 Hz, 2H), 7.40(d, J=8.66 Hz, 2H), 7.80 (br s, 1H), 8.55 (s, 1H). [M+H]=426.2.

Example 2126-(2,3-Difluoro-4-methoxybenzyl)-8-((3-hydroxyazetidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 1H), 7.82-7.89 (m, 1H), 7.21-7.29(m, 1H), 6.96-7.04 (m, 1H), 6.09-6.27 (m, 1H), 5.40 (s, 2H), 4.63 (br s,2H), 4.37-4.52 (m, 1H), 4.15-4.33 (m, 2H), 3.81-3.96 (m, 5H).[M+H]=433.9.

Example 2136-(2-Fluoro-4-methoxybenzyl)-8-((3-hydroxyazetidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.83-7.89 (m, 1H), 7.37 (t,J=8.85 Hz, 1H), 6.92 (dd, J=12.49, 2.45 Hz, 1H), 6.76 (dd, J=8.66, 2.38Hz, 1H), 5.36 (s, 2H), 4.64 (br s, 2H), 4.39-4.51 (m, 1H), 4.17-4.31 (m,2H), 3.89-3.99 (m, 2H), 3.76 (s, 4H). [M+H]=415.9.

Example 2146-(2,3-Difluoro-4-methoxybenzyl)-8-((dimethylamino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H), 7.74 (s, 1H), 7.15-7.24 (m, 1H),6.69-6.79 (m, 1H), 5.44 (s, 2H), 4.51 (s, 2H), 3.89 (s, 3H), 2.89 (s,6H). [M+H]=not observed.

Example 2159-((Diisopropylamino)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.33 (d, J=6.40 Hz, 5H), 1.41 (d, J=6.65 Hz,5H), 3.75 (s, 3H), 3.77-3.85 (m, 2H), 4.81 (d, J=5.65 Hz, 2H), 5.39 (s,2H), 6.95 (d, J=8.66 Hz, 2H), 7.43 (d, J=8.53 Hz, 2H), 7.75 (s, 1H),8.68 (s, 1H). [M+H]=426.2.

Example 216 was made in a manner analogous to Example 82, with theappropriate starting material and reagent substitutions.

Example 2166-(4-Methoxybenzyl)-10-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,4′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, CDCl₃) δ 1.35 (qd, J=12.30, 4.39 Hz, 2H), 1.62-1.73 (m,2H), 1.93 (ddt, J=15.04, 7.51, 3.84, 3.84 Hz, 1H), 1.98-2.09 (m, 2H),2.91-3.05 (m, 4H), 3.18-3.28, (m, 2H), 3.34-3.47 (m, 2H), 3.78 (s, 3H),4.01 (dd, J=11.42, 3.51 Hz, 2H), 5.28 (s, 2H), 6.86 (d, J=8.66 Hz, 2H),7.41 (d, J=8.53 Hz, 2H), 8.27 (s, 1H). [M+H]=466.2.

Example 217 was made in a manner analogous to Example 99, with theappropriate starting material and reagent substitutions.

Example 2176-(4-Methoxybenzyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.68-1.78 (m, 2H), 3.03-3.13 (m, 2H),3.37-3.44 (m, 2H), 3.74 (s, 3H), 3.85-3.92 (m, 2H), 5.29 (s, 2H), 6.92(d, J=8.53 Hz, 2H), 7.36 (d, J=8.53 Hz, 2H), 8.50 (s, 1H). [M+H]=382.2.

Example 218 was made in a manner analogous to Example 43, with theappropriate starting material and reagent substitutions.

Example 21811,11-Difluoro-9-isobutyl-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 0.88 (d, J=6.40 Hz, 1H), 1.79-1.95 (m, 1H),2.37 (d, J=7.28 Hz, 2H), 3.19 (t, J=11.86 Hz, 1H), 3.74 (s, 3H),3.77-3.83 (m, 2H), 5.36 (s, 2H), 6.93 (d, J=8.53 Hz, 2H), 7.38 (d,J=8.41 Hz, 2H), 8.52 (s, 1H). [M+H]=460.2.

Examples 219 and 220 were made in a manner analogous to Example 99, withthe appropriate starting material and reagent substitutions.

Example 21911,11-Difluoro-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 3.75 (s, 3H), 3.80-3.91 (m, 2H), 4.29-4.39(m, 2H), 5.40 (s, 2H), 6.94 (d, J=8.53 Hz, 2H), 7.39 (d, J=8.66 Hz, 2H),8.55 (s, 1H). [M+H]=404.2.

Example 2206-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 1.78-1.90 (m, 2H), 2.84-2.91 (m, 2H),3.13-3.25 (m, 2H), 3.74 (s, 3H), 5.25 (s, 2H), 5.91-5.98 (m, 1H), 6.92(d, J=8.53 Hz, 2H), 7.32 (d, J=8.66 Hz, 2H), 8.44 (s, 1H). [M+H]=368.2.

PDE1b Inhibitory Assay Assay Conditions

PDE1b inhibition was determined by an IMAP TR-FRET assay. The IMAPTR-FRET PDE assay was optimized for concentration of enzyme, Calmodulin,cAMP or cGMP substrate, DMSO tolerance, and incubation time.

Into each well of a solid white 1536 well plate (Corning) was dispensed250 pg full-length recombinant NH-terminal GST tagged human PDE1b enzyme(BPS Bioscience Cat #60011, San Diego, Calif.) in 2.5 μL IMAP BSAreaction buffer (Molecular Devices, Sunnyvale, Calif.) containing 10U/mL Calmodulin and 2.5 mM CaCl₂ (Sigma Aldrich.) After a briefcentrifugation, 30 nL compound was added by transfer from 1 mM stock inDMSO using a Kalypsys 1536 Pintool. Plates were incubated for 5 minutesat room temperature before dispensing 1.5 μL of 533 nM 5-carboxyfluorescein (FAM)-labeled cAMP (Molecular Devices, Sunnyvale, Calif.)for a final concentration of 200 nM. After a brief centrifugation, theplates were incubated for 30 minutes at room temperature. The assay wasterminated by adding 5 μL IMAP binding reagent/Tb complex (MolecularDevices, Sunnyvale, Calif.) to each well.

Plates were incubated 1 hour at room temperature and read on a Viewluxmultimode plate reader (Perkin Elmer). The instrument was set to exciteusing the DUG11 filter and measure using 490/10 nm and 520/10 nmfilters. Ratios of acceptor and donor were then calculated.

Data Analysis

For EC₅₀ calculations, the values of % efficacy versus a series ofcompound concentrations were then plotted using non-linear regressionanalysis of sigmoidal dose-response curves generated with the equationY=B+(T−B)/1+10((Log EC50−X)×Hill Slope), where Y=percent activity,B=minimum percent efficacy, T=maximum percent efficacy, X=logarithm ofcompound and Hill Slope=slope factor or Hill coefficient. The EC₅₀ valuewas determined by the concentration causing a half-maximal percentefficacy.

Results

Table presents the negative log of the half-maximal molar inhibitoryconcentration (pEC₅₀), with respect to PDE1b activity, for compounds ofFormula (I).

PDE1b (pEC₅₀) Example Numbers >7 29, 31, 33, 34, 35, 36, 37, 38, 39, 40,41, 44, 45, 46, 47, 48, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 73, 74, 75, 80, 90, 103, 104,105, 106, 108, 109, 110, 111, 112, 113, 115, 116, 117, 118, 119, 120,121, 122, 123, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135,136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149,150, 156, 157, 158, 159, 160, 161, 162, 164, 165, 166, 167, 168, 169,170, 171, 172, 173, 174, 175, 179, 186, 187, 189, 191, 193, 194, 199,201, 202, 203, 205, 206, 207, 209, 217, 219, 220 6-7 3, 5, 6, 8, 9, 11,15, 17, 22, 23, 25, 26, 27, 28, 30, 32, 42, 43, 49, 72, 76, 77, 78, 79,82, 83, 84, 85, 87, 88, 91, 93, 94, 95, 101, 102, 104, 107, 114, 124,151, 152, 163, 180, 181, 182, 183, 184, 185, 188, 192, 195, 197, 208,210, 211, 212, 213, 214, 215, 218, 221 5-6 1, 2, 10, 12, 13, 16, 18, 19,20, 24, 81, 86, 89, 92, 96, 97, 99, 100, 153, 155, 176, 190, 196, 198,200, 204 <5 4, 7, 14, 21, 98, 177, 178, 216

PDE1 Selectivity of Compounds Assay Conditions

The selectivity of compounds of the present invention was determinedusing a panel of recombinant human PDEs and an in vitro enzymatic assay(BPS Bioscience). Series of dilutions of each test compound wereprepared with 10% DMSO in assay buffer and 5 μL of the dilution wasadded to a 50 μL reaction so that the final concentration of DMSO is 1%in all of reactions.

The enzymatic reactions were conducted at room temperature for 60minutes in a 50 μL mixture containing PDE assay buffer, 100 nM FAM-cAMP,or 100 nM FAM-cGMP, a recombinant PDE enzyme and the test compound.

After the enzymatic reaction, 100 μL of a binding solution (1:100dilution of the binding agent with the binding agent diluent) was addedto each reaction and the reaction was performed at room temperature for60 minutes.

Fluorescence intensity was measured at an excitation of 485 nm and anemission of 528 nm using a Tecan Infinite M1000 microplate reader.

Data Analysis

PDE activity assays were performed in duplicate at each concentration.Fluorescence intensity is converted to fluorescence polarization usingthe Tecan Magellan6 software. The fluorescence polarization data wereanalyzed using the computer software, Graphpad Prism. The fluorescencepolarization (FPt) in absence of the compound in each data set wasdefined as 100% activity. In the absence of PDE and the compound, thevalue of fluorescent polarization (FPb) in each data set was defined as0% activity. The percent activity in the presence of the compound wascalculated according to the following equation: %activity=(FP−FPb)/(FPt−FPb)×100%, where FP=the fluorescence polarizationin the presence of the compound.

For IC₅₀ calculations, the values of % activity versus a series ofcompound concentrations were then plotted using non-linear regressionanalysis of Sigmoidal dose-response curve generated with the equationY=B+(T−B)/1+10((Log EC50−X)×Hill Slope), where Y=percent activity,B=minimum percent activity, T=maximum percent activity, X=logarithm ofcompound and Hill Slope=slope factor or Hill coefficient. The IC₅₀ valuewas determined by the concentration causing a half-maximal percentactivity.

Results

Exemplary compounds of the present invention displayed selectivity forPDE1 enzymes versus isoforms from many, if not all, other PDE families.In addition, exemplary compounds showed greater specificity for PDE1bcompared to PDE1a and PDE1c.

Biological Examples

The present disclosure will be further illustrated by the followingbiological examples. These examples are understood to be exemplary only,and not to limit the scope of the invention disclosed herein.

Biological Example 1 Effect of siRNA Mediated Knockdown of PDE1B onMemory Formation

The role of pde1b in memory formation in animals was evaluated by RNAinterference. See, e.g., Peters et al., 2009, Genes Brain Behav. 8,320-329. The results showed that siRNA-mediated inhibition of pde1b inanimals enhanced several forms of long-term memory, including contextualand temporal (trace) memory.

Procedures

siRNA

Initially, several non-modified siRNAs were tested for pde1a and pde1bknockdown in vitro using Neuro 2a cells. The siRNAs were specific to thePde1 isoforms as identified by BLAST search. Several siRNAs showedefficacy in reducing pde1b mRNA levels and were chosen for further invivo characterization. The behavioral studies used in vivo gradesiSTABLE siRNA, which was chemically modified to enhance stability(Dharmacon Inc., Lafayette, USA). The sequence of the pde1b-6 siRNAsense strand was: 5′-GCUACAUGGUGAAGCAGUU-3′(SEQ ID NO: 1). The sequenceof the non-targeting, control siRNA sense strand was:5′-UAGCGACUAAACACAUCAAUU-3′(SEQ ID NO: 2).

Subjects

Young-adult (12-16 weeks old) C57BL/6Jax (Jackson Laboratories) malemice were utilized for contextual conditioning and C57Bl/6NTac (TaconicFarms) mice for trace fear conditioning. Upon arrival, mice weregroup-housed (5 mice) in standard laboratory cages and maintained on a12:12 hours light-dark cycle. Experiments were always conducted duringthe light phase of the cycle.

After surgery for hippocampal cannulation, mice were housed inindividual cages for the duration of the experiment. Mice received foodand water ad libitum except when being trained or tested. They weremaintained and bred under standard conditions, consistent with NationalInstitutes of Health (NIH) guidelines and approved by the InstitutionalAnimal Care and Use Committee.

Animal Surgery

For both contextual and trace conditioning, mice were infused withnon-targeting or Pde1b siRNA into the hippocampus. For the injection ofsiRNA, mice were anesthetized with 20 mg/kg Avertin and implanted with a33-gauge guide cannula bilateraly into the dorsal hippocampus(coordinates: A=−1.8 mm, L=+/−1.5 mm to a depth of 1.2 mm) or intoamygdala (coordinates: A=−1.58 mm, L=+/−2.8 mm to a depth of 4.0 mm)(Franklin and Paxinos, The Mouse Brain in Stereotaxic Coordinates.Academic Press, San Diego 2003). Five to nine days after recovery fromsurgery, animals were injected with siRNA diluted to 0.5 μg/μl in 5%glucose and mixed with 6 equivalents of a 22 kDa linearpolyethyleneimine (Fermentas). After 10 min of incubation at roomtemperature, 2 μl were injected into each hippocampus through aninfusion cannula that was connected to a micro-syringe by a polyethylenetube. Animals were handled gently to minimize stress.

A total of 3 infusions of siRNA were given over a period of 3 days (1 μgsiRNA per hippocampus per day). Mice were trained 3 days after the lastsiRNA injection and tested 24 hours later. Behavioral testing wasinitiated 3 days later. This design was chosen based on pilotexperiments on siRNA knockdown in hippocampus, and because previousstudies have indicated that gene-knockdown by siRNA duplexes takesseveral days to develop in CNS. See, e.g., Salahpour et al., 2007, Biol.Psychiatry 61, 65-69; Tan et al., 2005, Gene Therapy 12, 59-66; Thakkeret al., 2004, Proc. Natl. Acad. Sci. USA 101, 17270-17275.

Fear Conditioning

Rationale

Contextual fear conditioning is a form of associative learning in whichanimals learn to recognize a training environment (conditioned stimulus,CS) that has been previously paired with an aversive stimulus such asfoot shock (unconditioned stimulus, US). When exposed to the samecontext at a later time, conditioned animals show a variety ofconditional fear responses, including freezing behavior. See, e.g.,Fanselow, 1984, Behav. Neurosci. 98, 269-277; Fanselow, 1984, Behav.Neurosci. 98, 79-95; Phillips and LeDoux, 1992, Behav. Neurosci. 106,274-285.

Contextual conditioning has been used to investigate the neuralsubstrates mediating fear-motivated learning. See, e.g., Phillips andLeDoux, 1992, Behav. Neurosci. 106, 274-285; Kim et al., 1993, Behav.Neurosci. 107, 1093-1098. Recent studies in mice and rats providedevidence for functional interaction between hippocampal andnon-hippocampal systems during contextual conditioning training See,e.g., Maren et al., 1997, Behav. Brain Res. 88, 261-274; Maren et al.,1997, Neurobiol. Learn. Mem. 67, 142-149; Frankland et al., 1998, Behav.Neurosci. 112, 863-874. Specifically, post-training lesions of thehippocampus (but not pre-training lesions) greatly reduced contextualfear, implying that: 1) the hippocampus is essential for contextualmemory but not for contextual learning per se and 2) in the absence ofthe hippocampus during training, non-hippocampal systems can supportcontextual conditioning.

Contextual conditioning has been extensively used to study the impact ofvarious mutations on hippocampus-dependent learning and memory andstrain differences in mice. See, e.g., Bourtchouladze et al., 1994, Cell79, 59-68; Bourtchouladze et al., 1998, Learn Mem. 5, 365-374; Kogan etal., 1997, Current Biology 7, 1-11; Silva et al., 1996, Current Biology6, 1509-1518; Abel et al., 1997, Cell 88, 615-626; Giese et al., 1998,Science 279, 870-873; Logue et al., 1997, Neuroscience 80, 1075-1086;Chen et al., 1996, Behav. Neurosci. 110, 1177-1180; Nguyen et al., 2000,Learn Mem. 7, 170-179.

Because robust learning can be triggered with a few minutes trainingsession, contextual conditioning has been especially useful to study thebiology of temporally distinct processes of short- and long-term memory.See, e.g., Kim et al., 1993, Behav. Neurosci. 107, 1093-1098; Abel etal., 1997, Cell 88, 615-626; Bourtchouladze et al., 1994, Cell 79,59-68; Bourtchouladze et al., 1998, Learn. Mem. 5, 365-374. As such,contextual conditioning provides an excellent model to evaluate the roleof various novel genes in hippocampal-dependent memory formation.

Protocol

Previous investigations had established that training with 1× or 2×CS-US pairings induces sub-maximal (weak) memory in wild-type mice. See,e.g., U.S.2009/0053140; Tully et al., 2003, Nat. Rev. Drug Discov. 2,267-77; Bourtchouladze et al. 1998, Learn. Mem. 5, 365-374. Accordingly,contextual conditioning in this study was performed as described byBourtchouladze et al., 1994, Cell 79, 59-68.

An automated fear conditioning system (Colburn Instruments) was used forcontextual conditioning and a manual setup (Med Associates) for tracefear conditioning. Mice were placed in the conditioning chamber andallowed to explore for 2 min. A total of two foot-shocks were delivered(0.6 mA, 2 s duration) with an inter-trial interval of 1 min. Freezingwas scored for 30 s after the last foot-shock (immediate freezing). Micewere then returned to their home-cage. Memory was tested after 24 h(LTM). To assess contextual memory, freezing behavior was scored for 3min intervals of 1 s in the chamber in which the mice were trained

Trace Conditioning

Rationale

Trace fear conditioning is a form of Pavlovian conditioning, in which aninterval of time passes between CS termination and UCS onset. Thus, theCS and US are separated in time by a trace interval, and the memory ofthis temporal relationship requires the hippocampus and prefrontalcortex. See Knight et al., 2004, J. Neurosci. 24, 218-228.

Trace conditioning becomes increasingly difficult as the time intervalbetween CS and US increases. For example, C57BL/6 mice show poor memoryif the trace interval between CS and US is 60 seconds or longer. See,e.g., U.S.2009/0053140. Moreover, previous studies have demonstratedthat this memory impairment can be overcome if mice are treated withsiRNA against PP1, a negative regulator of plasticity in thehippocampus. Peters et al., 2009, Genes Brain Behav. 8, 320-329.Consequently, the trace conditioning assay provides a method to test theability of a compound to facilitate hippocampal-dependent memory.

Protocol

Facilitation of temporal memory in this study was assessed using asingle CS-US pairing with a 60 s trace interval. For this study,standardized mouse contextual fear conditioning equipment was used (MedAssociates, Inc., VA; Bourtchouladze et al., 1994, Cell 79, 59-68;(Bourtchouladze et al., 1998 Learn Mem. 5, 365-374). On the trainingday, the mouse was placed into the conditioning chamber for 2 minutesbefore the onset of the conditioned stimulus (CS), a 2800 Hz tone, whichlasted for 20 seconds at 75 dB. Sixty seconds after the end of the tone,a 0.5 mA shock unconditioned stimulus (US) was delivered to the animalfor two seconds. Following an additional 30 s in the chamber, the mousewas returned to its home cage.

Mice were tested at 24 h after training in a novel chamber located inanother procedural room to avoid confounding effects of contextualconditioning. The internal conditioning chamber was removed and replacedwith a mouse cage. Different colored tape was placed on the backside ofeach cage to differentiate one from another. Three different cages wereused in rotation in order to decrease the possibility of scentcontamination from subject to subject. A 30-watt lamp was placed insidethe chamber to insure difference in illumination between training andtesting. The cages were cleaned using a soapy solution instead ofethanol.

Each test began with two minutes of light only (pre-CS), then 20 secondsof tone presentation (CS), followed by an additional 30 seconds of lightonly (post-CS). In the same manner as during training, the mice werescored one at a time for “freezing” in five-second intervals, as forcontextual conditioning described above. The proceeding of eachexperiment was filmed. The proportion of the freezing response specificto the auditory memory was determined by subtraction of preCS freezing(non-specific) from CS freezing (CS−preCS).

Statistical Analyses

All behavioral experiments were designed and performed in a balancedfashion: First, for each experimental condition (e.g., a specific doseeffect) an equal number of experimental and control mice were used.Second, each experimental condition was replicated several times andreplicate days were added to generate final number of subjects. Third,each session was video recorded and the experimenter was unaware (blind)to the treatment the subjects during training and testing.

Data were analyzed by ANOVA using JMP software. Except where indicated,all values in the text and figures are expressed as mean+SEM.

Results

Contextual Memory

When tested in contextual fear conditioning with 2 CS-US pairings toinduce weak (sub-maximal) contextual memory, pde1b siRNA-injected miceshowed significantly enhanced freezing 24 hours after training, comparedto non-targeting siRNA-injected mice (FIG. 1).

Trace Memory

Similarly, when tested in trace conditioning with one CS/US pairing anda 60-s trace interval, pde1b siRNA-injected mice showed enhanced tracememory (FIG. 2). Repeated measures ANOVA revealed a significanttreatment-by-trial interaction (p<0.05). Contrast analysis revealed thatpde1b siRNA and control mice froze an equal proportion of time to tone(CS: p=0.13, preCS: p=0.54). However, only pde1b siRNA-treated miceformed a memory for the CS, while mice treated with control siRNA didnot (effect of tone CS: p<0.05 and p=0.62 for pde1b and control siRNA,respectively). Moreover, pde1b treated mice showed significantly higherfreezing if the nonspecific freezing in the alternate testing contextwas subtracted from the response to tone CS (CS−preCS: p<0.05). Thus,siRNA-mediated knockdown of hippocampal pde1b enhanced memory formationafter trace fear conditioning as observed for contextual fearconditioning.

Taken together these results show that Pde1b is a negative regulator ofmemory formation in the hippocampus, a temporal lobe structure that iscritical to memory formation in mice as well as in humans. Importantly,Pde1b siRNA induced a ‘gain of function’ (that is, enhancement ofcontextual and temporal memory formation). Hence these results show thatPde1b is a valid target for enhancing cognition, and memoryspecifically.

Biological Example 2 Effect of siRNA Mediated Knockdown of PDE1 onNeurite Growth

In the mouse, pde1b is highly expressed in the dentate gyrus andolfactory bulb, the two areas where neurogenesis occurs in the adultnervous system. Neurogenesis is the process by which new neurons areborn and undergo dendritic and synaptic differentiation to integratewith functional circuitry. Neurogenesis in the hippocampus has beenimplicated in memory formation. See, e.g., Shors et al., 2001, Nature410, 372-376; Shors et al., 2004, Trends Neurosci. 27, 250-256. Thestudies here evaluated the effect of pde1b inhibition of neuriteoutgrowth in the PC12 subclone NS1 (Cellomics). Neurite outgrowth (NOG)in PC12 cells (and primary neurons) occurs upon activation of signalingpathways that act through CREB. See, e.g., Greene and Tischler, 1976,Proc. Natl. Acad. Sci. USA 73, 2424-2428; Cheng et al., 2002, J. Biol.Chem. 277, 33930-33942.

This study evaluated the effect on neurite outgrowth (NOG) of drugsknown to enhance cAMP-mediated activation of CREB, i.e., the PDE4inhibitor rolipram—and compared these effects with those induced bysiRNA-mediated inhibition of pde1b.

Methods

Cell Culture

Neuroscreen 1 (NS1) Cells (Cellomics Inc.) were cultured on collagentype I coated 75 cm2 plastic flasks (Biocoat, Becton Dickinson) in ahumidified incubator at 37° C. in 5% CO2. Cells were cultured in RPMIcomplete cell culture medium (Cambrex) supplemented with 10%heat-inactivated horse serum (Invitrogen), 5% heat-inactivated fetalbovine serum (Cellgro), and 2 mM L-glutamine (Cambrex). For expansion,the cells were trypsinized and split at 80% confluence. Cell culturemedia was changed every 2 to 3 days.

NS1 cells were harvested and counted using a Coulter counter (BectonDickinson Coulter Z1). Cells were seeded in 96-well collagen I coatedplates at a density of 2000 cells per well in volume of 200 μl. RPMImedia was supplemented with 200 ng/ml nerve growth factor (NGF, Sigma).NS1 cells were incubated for 72 hours to allow differentiation to aneuronal phenotype. NGF as then diluted to 50 ng/ml and the cells weretreated with siRNA or compound at the indicated doses in FIG. 2A.

Neurite Outgrowth Assay

Neurite outgrowth (NOG) assays were performed using the CellomicsArrayscan II Vti HCS scanner. Cells were stained using the HitKit™ HCSreagent kit (Cellomics) according to the manufacturer's instructions(which were previously validated for specific labeling of both neuritesand neuronal cell bodies. Briefly, cells were fixed in 3.7% formaldehydeand stained with Hoechst dye to label the nuclei. The cells were thenwashed in neurite outgrowth buffer, incubated for one hour with theprimary antibody for neurite outgrowth (anti-tubulin III), washed again,and incubated with fluorescently labeled secondary antibody solution for1 hr.

Antibody-stained 96-well plates were stored at 4° C. in the dark untilscanning. Plates were scanned using Cellomics ArrayScan II Vti HCSscanner. The neurite outgrowth assay is based on two channels toscanning: (1) Channel 1, which detects the Hoechst Dye and is used bythe software to identify cells and for automated focusing; and (2)Channel 2, which detects the FITC fluorescence of the secondary antibodyand is used by the software to calculate all data generated in referenceto neurites.

siRNA and Drug Administration

The pde1b-specific siRNAs were the same as those described in BiologicalExample 1. The adenylyl cyclase stimulator forskolin and the selectivePDE4 small molecule inhibitor Rolipram were administered at the dosesindicated in FIG. 3A.

Results

As shown in FIG. 3A, neurite length and branching in NS1 cells wasenhanced in dose-dependent manner by acute treatment with Rolipram andforskolin—but was not affected by treatment with Rolipram alone.Similarly, FIG. 3B shows that neurite outgrowth in NS1 cells wasenhanced by siRNA-mediated knockdown of pde4d (the target of Rolipram)or pde1b in combination with forskolin. In contrast to Rolipram (whichlikely only inhibits PDE4 for several hours), pde4d and pde1b siRNAadministration (>48 h) each had a small effect on NOG without theaddition of Forskolin.

These results demonstrate that Pde1b inhibition leads to a functionalenhancement of neurite growth in NS1 cells. Accordingly, the NOG assayalso offers a suitable secondary (cellular/phenotypic) assay to testPde1b inhibitors identified from a high throughput screening campaign.

Biological Example 3 Effect of Exemplary Compounds on Memory

The studies here evaluated the effect of exemplary compounds of thepresent invention on memory and on haloperidol induced catalepsy in miceand rats

Methods

Subjects

Three month old B6129F1/J hybrid male mice (Jackson Laboratories, BarHarbor, Me.) male mice were utilized for contextual conditioning fearconditioning and novel object recognition studies and C57BL/6J males(Jackson Laboratories) were used for catalepsy studies. Outbred hoodedLong Evans rats (200 g average weight, Harlan) were used for rat objectrecognition and fear conditioning. Upon arrival, mice were group-housed(4 mice/cage) in Inovive IVC racks and maintained on a 12:12 hourslight-dark cycle. Rats were house in standard cages in groups of two.Experiments were always conducted during the light phase of the cycle.The animals received food and water ad libitum except during trainingand testing. All procedures were consistent with National Institutes ofHealth (NIH) guidelines and approved by the DNS/Helicon InstitutionalAnimal Care and Use Committee.

Drug Administration

Pde1 inhibitors and positive control were dosed in a Vehicle containing10% DMSO, 30% PEG (MW400) and 60% PBS, unless specified otherwise. Forsubcutaneous dosing (s.c.), all drugs were administered at a volume of10 ml per kg 30 min prior to behavior training unless specifiedotherwise. For oral dosing (p.o.), animals were dosed at the indicatedamount 30 minutes prior to training.

Contextual Conditioning

Protocol

Contextual conditioning was essentially carried out as described inBiological Example 1. An automated fear conditioning system (ColburnInstruments) was used for contextual conditioning and a manual setup(Med Associates) for trace fear conditioning. Mice were placed in theconditioning chamber and allowed to explore for 2 min. A total of twofoot-shocks were delivered (0.2 mA, 2 s duration) with an inter-trialinterval of 1 min. As previously noted, these training conditionsgenerate sub-maximal, or weak, memory in control mice, thereby allowingone to evaluate whether a Pde1b compound of the present invention canenhance memory formation.

Freezing was scored for 30 s after the last foot-shock (immediatefreezing). The mice were then returned to their home-cage. Memory wastested after 24 h (LTM) for 3 min by scoring freezing behavior inintervals of is in the chamber in which the mice were trained.

Object Recognition Memory

Rationale

Novel Object Recognition (NOR) is an assay of recognition learning andmemory retrieval, which takes advantage of the spontaneous preference ofrodents to investigate a novel object compared with a familiar one.

The NOR test has been employed extensively to assess the potentialcognitive-enhancing properties of novel compounds derived fromhigh-throughput screening. Object recognition is an ethologicallyrelevant task that does not result from negative reinforcement (footshock). This task relies on the natural curiosity of rodents to explorenovel objects in their environments more than familiar ones. Obviously,for an object to be “familiar,” the animal must have attended to itbefore and remembered that experience. Hence, animals with better memorywill attend and explore a new object more than an object familiar tothem. During testing, the animal is presented with the training objectand a second, novel one. Memory of the training object renders itfamiliar to the animal, and it then spends more time exploring the newnovel object rather than the familiar one. See Bourtchouladze et. al.,2003, Proc. Natl. Acad. Sci. USA 100, 10518-10522).

Studies indicate that the NOR procedure involves several brain regions,including the cortex and the hippocampus. Recent neuroimaging studies inhumans demonstrated that memory in object recognition depends onprefrontal cortex (PFC). See Delbert et al., 1999, Neurology 52,1413-1417. Consistent with these findings, rats with the PFC lesionsshow poor working memory when they are required to discriminate betweenfamiliar and novel objects. See Mitchell, 1998, Behav. Brain Res. 97,107-113. Other studies on monkeys and rodents suggest that thehippocampus is important for novel object recognition. See, e.g., Tenget al., 2000, J. Neurosci 20, 3853-3863; Mumby, 2001, Brain Res. 127,159-181. Hence, object recognition provides an excellent behavioralmodel to evaluate drug-compound effects on cognitive task associatedwith function of the hippocampus and cortex.

Protocol

The novel object recognition task was performed as described by Bevinsand Besheer, 2006 (Nat. Protocol. 1, 1306-1311) using a standard novelobject recognition system for rats (Stoelting). Objects were placed inthe center of the box, testing was carried out in low light, and timeexploring objects was assessed using Ethovision Software. All videoswere reviewed by trained observers.

For two consecutive days, rats were habituated to the chamber for 5 minwith 5 min of handling immediately following exposure to the apparatus.The next day, rats treated with 10% DMSO, 30% PEG400, 60% Saline vehicleor compound 30 min before training were exposed to either two whiteblocks or two grey balls (˜4 cm in width/diameter) for 3 min. Aperformance control group was treated with vehicle and exposed to objectfor 15 min. Approximately 24 h after training, rats were exposed to onefamiliar object and one novel object (grey ball is replaced with a whiteblock and vice versa) and the time exploring each object was measured.Memory was scored by calculation of a discrimination index((T_(N)−T_(F))/(T_(N)+T_(F)))*100; between group comparison) and bycomparison of the time exploring the novel versus familiar object on thetest day (within group comparison).

Statistical Analyses

All behavioral experiments were designed and performed in a balancedfashion: (i) For each experimental condition (e.g. a specificdose-effect) an equal number of experimental and control mice were used;(ii) Each experimental condition was replicated several times, and (iii)Replicate days were added to generate final number of subjects. Theproceeding of each session was filmed. In each experiment, theexperimenter was unaware (blind) to the treatment of the subjects duringtraining and testing. Data were analyzed by ANOVA using JMP software,followed by contrast analysis.

Data were transformed using box-cox transformation, and the results ofcontrast analysis comparing treatment groups to vehicle are shown (LSmeans students-t). Except were indicated, all values in the text andfigures are expressed as Mean±SEM.

Results

Exemplary compounds of Formula I were found to significantly enhance 24hour memory, and where tested, to enhance 48 hour memory, in the objectrecognition assay. Control experiments showed that compoundadministration did not significantly affect the cumulative distancetraveled or amount of time spent exploring the left and right halves ofthe box. Significant effects were seen at several concentrations,depending on the compound, including concentrations of 0.1 mg/kg and 1mg/kg.

Exemplary compounds were also found to enhance contextual memory in thefear conditioning assay. Significant effects were seen at severalconcentrations, depending on the compound, including 0.01 mg/kg, 0.03mg/kg, and 1.0 mg/kg.

Biological Example 4 Effect of Exemplary Compounds on Cardiac Function

Exemplary compounds of the present invention were also evaluated inseveral models of cardiovascular function, in both guinea pigs and intelemeterized male rats. Each test compound (or vehicle) wasadministered by oral gavage, and animals were evaluated after each dosefor any abnormal clinical signs. Systemic blood pressure (systolic,diastolic, and mean arterial pressure), HR and pulse pressure wererecorded following dosing.

The results showed no notable effects of vehicle administration onsystemic blood pressure, heart rate, or arterial pulse pressure in thesestudies. All parameters were within expected range during the entiremonitoring period. In contrast, however, administration of several testcompounds let to a reduction in blood pressure, and in some cases,prolongation of the QTc interval.

It will be understood by one skilled in the art that the describedembodiments herein do not limit the scope of the invention. Thespecification, including the examples, is intended to be exemplary only,and it will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention as definedby the appended claims.

Furthermore, while certain details in the present disclosure areprovided to convey a thorough understanding of the invention as definedby the appended claims, it will be apparent to those skilled in the artthat certain embodiments may be practiced without these details.Moreover, in certain instances, well-known methods, procedures, or otherspecific details have not been described to avoid unnecessarilyobscuring aspects of the invention defined by the appended claims.

What is claimed is:
 1. A chemical entity of Formula I:

wherein: X is —CH— or —N—; Y is —O— or —S—; M is 0-5; R¹ is each independently selected from the group consisting of: H, halo, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₁₋₆thioalkyl, —C₁₋₆alkoxy, —C₁₋₆haloalkoxy, —SO₂C₁₋₆alkyl, aryl, heteroaryl, and heterocycloalkyl; R³ and R⁴ are each independently selected from the group consisting of —H, halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —CH₂OH, —C₁₋₆alkoxy, —C₁₋₆haloalkoxy, aryl, optionally substituted 5 or 6 membered heteroaryl, —(C₁-C₆alkyl)aryl, —(C₁-C₆ alkyl)heteroaryl, and —(CR¹⁰R¹¹)₁₋₃NR¹²R¹³; or R³ and R⁴ taken together with the carbons to which they are attached form a saturated or unsaturated monocylic ring system, having the following structure:

or R³ is ((2R,6S)-2,6-dimethylmorpholin-4-yl)methyl, ((2S,6R)-2,6-dimethylmorpholin-4-yl)methyl, (1,4-oxazepan-4-yl)methyl, (1,4-oxazepan-4-ylmethyl), (2,2-dimethylmorpholino)methyl, (3-hydroxyazetidin-1-yl)methyl, (4-(methylsulfonyl)piperazin-1-yl)methyl, (4-acetyl-1,4-diazepan-1-yl)methyl, (4-acetylpiperazin-1-yl)methyl, (4-ethyl-3-oxopiperazin-1-yl)methyl, (4-methylpiperazin-1-yl)methyl, [3-(2-fluorophenoxy)azetidin-1-yl]methyl, [4-(2-fluorophenyl)piperazin-1-yl]methyl, [4-(3-fluorophenyl)piperazin-1-yl]methyl, [4-(4-fluorophenyl)piperazin-1-yl]methyl, [4-(morpholin-4-yl)piperidin-1-yl]methyl, [4-(pyridin-4-yloxy)piperidin-1-yl]methyl, {1,1-difluoro-5-azaspiro [2.4]heptan-5-yl}methyl, 2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl, 4-thiomorpholine-1,1-dione, 7-oxa-2-azaspiro[3.5]nonan-2-ylmethyl, or morpholinomethyl, and R⁴ is H or —CH₃; or R³ and R⁴ taken together with the carbons to which they are attached form a six member monocyclic ring system, wherein D is —N(R⁹)—, and R⁹ is H, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —SO₂CH₃, benzyl, benzoyl, (3-chlorobenzyl), (4-chlorobenzyl), (3-chlorobenzoyl), (4-chlorobenzoyl), (2-fluorobenzyl), (4-fluorobenzyl), (pyridin-2-yl), (pyridin-2-ylmethyl), (pyridin-4-ylmethyl), (pyrimidin-2-ylmethyl), (pyrimidin-4-ylmethyl), (pyrazine-2-carbonyl), cyclopropylmethyl, (cyclopropanecarbonyl), (2,2-difluorocyclopropanecarbonyl), (tetrahydro-2H-pyran-4-yl)methyl, (oxetan-3-yl), (3-methyloxetan-3-yl)methyl, (tetrahydrofuran-3-yl)methyl, (tetrahydrofuran-3-carbonyl), (tetrahydro-2H-pyran-2-yl)methyl, (tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-3-yl)methyl, (1-methyl-1H-imidazol-2-yl)methyl, (4-methylthiazol-5-yl)methyl, (5-methyl-1,3,4-thiadiazol-2-yl)methyl, (1,1-dioxidothietan-3-yl), (1,4-dioxan-2-yl)methyl), (5-oxotetrahydrofuran-2-yl)methyl, (1-methylpyrrolidine-3-carbonyl), (pyrrolidine-3-carbonyl), or (morpholin-2-ylmethyl); D is —O—, —N(R⁹)—, or a bond; m and n are each independently 0-4, with the proviso that the sum of m and n is 1-5 when D is —O—, —N(R⁹)—, or is 2-6 when D is a bond; and with the proviso that when D is a bond, R¹ is not —Cl in the para position; R⁵, R⁶, R⁷, R⁸, are each independently selected from the group consisting of: —H, —F, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —OH, —C₁₋₆alkoxy, —C₁₋₆haloalkoxy; R⁹ is selected from the group consisting of —H, —C₁₋₆alkyl, —C₁₋₆thioalkyl, —C₁₋₆haloalkyl, —CO₂C₁₋₆alkyl, —SO₂(C₁₋₆alkyl), —C₁₋₆alkyl(aryl), —C₁₋₆alkyl(C₃₋₆cycloalkyl), —C₁₋₆alkyl(heterocycloalkyl), —C₁₋₆alkyl(heteroaryl), heteroaryl, —CO(aryl), —CO(heteroaryl), —CO(heterocycloalkyl), —CO(C₃₋₆cycloalkyl), wherein each aryl, cycloalkyl, heterocycloalkyl, heteroaryl are optionally unsubstituted or substituted with a member each independently selected from the group consisting of —H, —Cl, —F, and —CH₃; R¹⁰ and R¹¹ are each independently selected from the group consisting of —H, —F, —C₁₋₆alkyl, —CF₃ and —OH; R¹² and R¹³ are each independently selected from the group consisting of —H, —C₁₋₆ alkyl, —C₃₋₆cycloalkyl, —C₁₋₆alkyl(aryl), —C₁₋₆alkyl(heteroaryl), —C₁₋₆alkyl(heterocycloalkyl), —CH₂CON(C₁₋₆alkyl)₂; or R¹² is H or —C₁₋₆alkyl and R¹³ is —CH₃, —CH₂CON(CH₃)₂, cyclopropyl, benzyl, 3-pyridyl, oxan-4-ylmethyl, 2,2-dimethyloxan-4-yl, (3-methyloxetan-3-yl)methyl, (tetrahydrofuran-2-yl)methyl or (tetrahydrofuran-3-yl)methyl; or R¹² is H, —C₁₋₆alkyl, R¹³ is —CH₃, —CH₂CON(CH₃)₂, cyclopropyl, benzyl, 3-pyridyl, (tetrahydrofuran-2-yl)methyl, (tetrahydrofuran-3-yl)methyl, oxan-4-ylmethyl, 2,2-dimethyloxan-4-yl or (3-methyloxetan-3-yl)methyl; or R¹² and R¹³ are taken together with the nitrogen to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more R¹⁴, where each R¹⁴ is independently selected from the group consisting of —H, —C₁₋₆alkyl, —CH₂OH, —OH, —COCH₃, —SO₂CH₃, —O-pyridyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, —O-phenyl, —O-(2-fluorophenyl), -morpholino, 1,1-difluoro-cyclopropyl, or two R¹⁴ members are taken together to form a —C₃₋₆heterocycloalkyl; or R¹² and R¹³ are taken together with the nitrogen to which they are attached to form a heterocycloalkyl ring selected from (2R,6S)-2,6-dimethylmorpholine, (2S,6R)-2,6-dimethylmorpholine, (3R,5 S)-3,5-dimethylpiperazine, 1,1-difluoro-5-azaspiro[2.4]heptane, 1,4-oxazepane, 2-(methoxymethyl)pyrrolidine, 2,2-dimethylmorpholine, 2,6-dimethylmorpholine, 2-ethylmorpholine, 2-methylmorpholine, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-(2-fluorophenoxy)azetidine, 3,3,4-trimethylpiperazine, 3,4-dimethylpiperazine, 3-hydroxyazetidine, 3-methylmorpholine, 3-oxopiperazine, 4-(2-fluorophenyl)piperazine, 4-(3-fluorophenyl)piperazine, 4-(4-fluorophenyl)piperazine, 4-(methylsulfonyl)piperazine, 4-(morpholin-4-yl)piperidine, 4-(pyridin-4-yloxy)piperidine, 4-acetyl-1,4-diazepane, 4-acetylpiperazine, 4-ethyl-3-oxopiperazine, 4-hydroxypiperidine, 4-isopropylpiperazine, 4-methyl-piperazine, 4-thiomorpholine-1,1-dione, 8-oxa-3-azabicyclo[3.2.1]octane, isoindoline, morpholine, octahydropyrrolo[1,2-a]pyrazine, piperazine, and pyrrolidine; wherein the chemical entity is selected from the group consisting of compounds of Formula (I), and pharmaceutically acceptable salts of compounds of Formula (I).
 2. The chemical entity of claim 1, wherein Y is —S—.
 3. The chemical entity of claim 1, wherein M is 1, 2 or
 3. 4. The chemical entity of claim 2, wherein R¹ is —OCH₃.
 5. The chemical entity of claim 2, wherein R¹ is —F, —Cl, —Br, —CF₃, —CN or —CHF₂.
 6. The chemical entity of claim 1, wherein R³ is H, —Br, —C₁₋₆alkyl, benzyl, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl and R⁴ is H or —CH₃.
 7. The chemical entity of claim 1, wherein R³ is —(CR¹⁰R¹¹)₁₋₃NR¹²R¹³ and R⁴ is H or —CH₃.
 8. The chemical entity of claim 1, wherein R³ is H, —Br, —C₁₋₅alkyl, benzyl, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, or —(CR¹⁰R¹¹)NR¹²R¹³, where R¹⁰ and R¹ are each H, R¹² is H or —C₁₋₆alkyl, R¹³ is —CH₃, —CH₂CON(CH₃)₂, cyclopropyl, benzyl, 3-pyridyl, oxan-4-ylmethyl, 2,2-dimethyloxan-4-yl, (3-methyloxetan-3-yl)methyl, (tetrahydrofuran-2-yl)methyl or (tetrahydrofuran-3-yl)methyl and R⁴ is H or —CH₃.
 9. The chemical entity of claim 1, wherein R³ is —(CR¹⁰R¹¹)NR¹²R¹³, where R¹⁰ and R¹¹ are each H, R¹² is H, —C₁₋₆alkyl, R¹³ is —CH₃, —CH₂CON(CH₃)₂, cyclopropyl, benzyl, 3-pyridyl, (tetrahydrofuran-2-yl)methyl, (tetrahydrofuran-3-yl)methyl, oxan-4-ylmethyl, 2,2-dimethyloxan-4-yl or (3-methyloxetan-3-yl)methyl and R⁴ is H or —CH₃.
 10. The chemical entity of claim 1, wherein R³ is H or —CH₃ and R⁴ is —(CR¹⁰R¹¹)₁₋₃NR¹²R¹³.
 11. The chemical entity of claim 1, wherein R³ is H or —CH₃, R⁴ is —(CR¹⁰R¹¹)NR¹²R¹³, where R¹⁰ and R¹¹ are each H, R¹² is H or —C₁₋₆alkyl, and R¹³ is —C₁₋₆alkyl or oxan-4-ylmethyl.
 12. The chemical entity of claim 1, wherein R³ or R⁴ is —(CR¹⁰R¹¹)₁₋₃NR¹²R¹³, R¹⁰ and R¹¹ are each independently H, —CH₃, or —OH, and R¹² and R¹³ are taken together with the nitrogen to which they are attached to form a heterocycloalkyl ring selected from (2R,6 S)-2,6-dimethylmorpholine, (2S,6R)-2,6-dimethylmorpholine, (3R,5S)-3,5-dimethylpiperazine, 1,1-difluoro-5-azaspiro[2.4]heptane, 1,4-oxazepane, 2-(methoxymethyl)pyrrolidine, 2,2-dimethylmorpholine, 2,6-dimethylmorpholine, 2-ethylmorpholine, 2-methylmorpholine, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-(2-fluorophenoxy)azetidine, 3,3,4-trimethylpiperazine, 3,4-dimethylpiperazine, 3-hydroxyazetidine, 3-methylmorpholine, 3-oxopiperazine, 4-(2-fluorophenyl)piperazine, 4-(3-fluorophenyl)piperazine, 4-(4-fluorophenyl)piperazine, 4-(methylsulfonyl)piperazine, 4-(morpholin-4-yl)piperidine, 4-(pyridin-4-yloxy)piperidine, 4-acetyl-1,4-diazepane, 4-acetylpiperazine, 4-ethyl-3-oxopiperazine, 4-hydroxypiperidine, 4-isopropylpiperazine, 4-methyl-piperazine, 4-thiomorpholine-1,1-dione, 8-oxa-3-azabicyclo[3.2.1]octane, isoindoline, morpholine, octahydropyrrolo[1,2-a]pyrazine, piperazine, and pyrrolidine.
 13. The chemical entity of claim 1, wherein R³ is ((2R,6S)-2,6-dimethylmorpholin-4-yl)methyl, ((2S,6R)-2,6-dimethylmorpholin-4-yl)methyl, (1,4-oxazepan-4-yl)methyl, (1,4-oxazepan-4-ylmethyl), (2,2-dimethylmorpholino)methyl, (3-hydroxyazetidin-1-yl)methyl, (4-(methylsulfonyl)piperazin-1-yl)methyl, (4-acetyl-1,4-diazepan-1-yl)methyl, (4-acetylpiperazin-1-yl)methyl, (4-ethyl-3-oxopiperazin-1-yl)methyl, (4-methylpiperazin-1-yl)methyl, [3-(2-fluorophenoxy)azetidin-1-yl]methyl, [4-(2-fluorophenyl)piperazin-1-yl]methyl, [4-(3-fluorophenyl)piperazin-1-yl]methyl, [4-(4-fluorophenyl)piperazin-1-yl]methyl, [4-(morpholin-4-yl)piperidin-1-yl]methyl, [4-(pyridin-4-yloxy)piperidin-1-yl]methyl, {1,1-difluoro-5-azaspiro[2.4]heptan-5-yl}methyl, 2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl, 4-thiomorpholine-1,1-dione, 7-oxa-2-azaspiro[3.5]nonan-2-ylmethyl, or morpholinomethyl, and R⁴ is H or —CH₃.
 14. The chemical entity of claim 1, wherein R³ is morpholinomethyl, (2,2-dimethylmorpholino)methyl, 2,6-dimethylmorpholino)methyl, ((2S,6R)-2,6-dimethylmorpholino)methyl, ((2R,6S)-2,6-dimethylmorpholin-4-yl)methyl, (4-(methylsulfonyl)piperazin-1-yl)methyl, 1-hydroxy-2-morpholinoethyl or 2-((2S,6R)-2,6-dimethylmorpholino)-1-hydroxyethyl, and R⁴ is H or —CH₃.
 15. The chemical entity of claim 1, wherein R⁴ is ((2S,6R)-2,6-dimethylmorpholino)methyl, ((2R,6S)-2,6-dimethylmorpholin-4-yl)methyl, [(3-phenoxypyrrolidin-1-yl)methyl], [3-(hydroxymethyl)-3-(2-methylpropyl)piperidin-1-yl]methyl, [ethyl(oxan-4-ylmethyl)amino]methyl, [methyl(oxan-4-ylmethyl)amino]methyl, [(oxan-4-ylmethyl)amino]methyl, or [bis(propan-2-yl)amino]methyl.
 16. The chemical entity of claim 1, wherein R³ and R⁴ taken together with the carbons to which they are attached form a six member monocyclic ring system, wherein D is —O—, and m is 1 and n is
 2. 17. The chemical entity of claim 1, wherein R³ and R⁴ taken together with the carbons to which they are attached form a six member monocyclic ring system, wherein D is —N(R⁹)—, and m is 0, 1, or 2 and n is 1, 2 or 3; with the proviso that the sum of m and n is 1-5.
 18. The chemical entity of claim 1, wherein R³ and R⁴ taken together with the carbons to which they are attached form a six member monocyclic ring system, wherein D is a bond and m and n are
 2. 19. The chemical entity of claim 1, wherein R⁵, R⁶, R⁷, R⁸, are each independently —H, —F, or —CH₃.
 20. The chemical entity of claim 1, wherein R³ and R⁴ taken together with the carbons to which they are attached form a six member monocyclic ring system, wherein D is —N(R⁹)—, and R⁹ is H, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —SO₂CH₃, benzyl, benzoyl, (3-chlorobenzyl), (4-chlorobenzyl), (3-chlorobenzoyl), (4-chlorobenzoyl), (2-fluorobenzyl), (4-fluorobenzyl), (pyridin-2-yl), (pyridin-2-ylmethyl), (pyridin-4-ylmethyl), (pyrimidin-2-ylmethyl), (pyrimidin-4-ylmethyl), (pyrazine-2-carbonyl), cyclopropylmethyl, (cyclopropanecarbonyl), (2,2-difluorocyclopropanecarbonyl), (oxetan-3-yl), (3-methyloxetan-3-yl)methyl, (tetrahydrofuran-3-yl)methyl, (tetrahydrofuran-3-carbonyl), (tetrahydro-2H-pyran-2-yl)methyl, (tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-3-yl)methyl, (1-methyl-1H-imidazol-2-yl)methyl, (4-methylthiazol-5-yl)methyl, (5-methyl-1,3,4-thiadiazol-2-yl)methyl, (1,1-dioxidothietan-3-yl), (1,4-dioxan-2-yl)methyl), (5-oxotetrahydrofuran-2-yl)methyl, (1-methylpyrrolidine-3-carbonyl), (pyrrolidine-3-carbonyl), or (morpholin-2-ylmethyl).
 21. The chemical entity of claim 1, wherein R³ and R⁴ taken together with the carbons to which they are attached form a six member monocyclic ring system, wherein each R⁵, R⁶, R⁷, R⁸, are independently —H and —F; D is —N(R⁹)—, and R⁹ is (tetrahydrofuran-3-yl)methyl or (tetrahydro-2H-pyran-4-yl)methyl.
 22. A compound selected from the group consisting of: 6-(2-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-Benzyl-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Benzyl-6-(2-chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Benzyl-6-(3-chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-Benzyl-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6, 8-Dibenzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)-8-benzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Benzyl-6-(4-chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-Benzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-Benzyl-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-8,9-dimethylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((1,4-Oxazepan-4-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Dimethylamino)methyl)-6-(4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-(morpholinomethyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((4-methylpiperazin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Ethyl-3-oxopiperazin-1-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((2,2-dimethylmorpholino)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(2-oxa-5-azabicyclo [2.2.1]heptan-5-ylmethyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(7-oxa-2-azaspiro [3.5]nonan-2-ylmethyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(2-Oxa-7-azaspiro [3.5]nonan-7-ylmethyl)-6-(4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 7-((6-(4-Methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-8-yl)methyl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3 (5H)-one; 6-(4-Methoxybenzyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(3,5-Dimethylisoxazol-4-yl)-6-(4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-(pyrrolidin-1-ylmethyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-(morpholinomethyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Dimethylamino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Cyclopropyl(methyl)amino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Hydroxypiperidin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Benzyl(2-hydroxyethyl)amino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-(piperazin-1-ylmethyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((((3-methyloxetan-3-yl)methyl)amino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Acetylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-(((pyridin-3-ylmethyl)amino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((3-oxopiperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((methyl((tetrahydrofuran-2-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(Isoindolin-2-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Cyclopropylamino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; (S)-6-(4-Methoxybenzyl)-8-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((methyl((tetrahydrofuran-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2-(((6-(4-Methoxybenzyl)-9-methyl-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-8-yl)methyl)(methyl)amino)-N,N-dimethylacetamide; 8-((1,4-Oxazepan-4-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((4-methylpiperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Isopropylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(2-Oxa-5-azabicyclo [2.2.1]heptan-5-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Ethyl-3-oxopiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(8-Oxa-3-azabicyclo [3.2.1]octan-3-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((2-Ethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((2,2-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((2-methylmorpholino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((3-methylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((3R,5 S)-3,5-Dimethylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((3,4-Dimethylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((3,3,4-trimethylpiperazin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; (S)-8-((Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Bromo-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(Hydroxymethyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-8,9-dimethylfuro[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; tert-Butyl 6-(4-methoxybenzyl)-5-oxo-5,6,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9(8H)-carboxylate; 6-(2-Chlorobenzyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 4-(4-Methoxybenzyl)-2-(morpholinomethyl)pyrazolo[1,5-c]thieno [3,2-e]pyrimidin-5(4H)-one; 6-(4-Chlorobenzyl)-10,10-dimethyl-6, 8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-Benzyl-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chlorobenzyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Methylbenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-(Trifluoromethyl)benzyl)-6, 8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Methoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(3,4-Dichlorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Fluorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Chloro-3-fluorobenzyl)-6, 8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Chloro-2-fluorobenzyl)-6, 8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(3-Fluoro-4-methoxybenzyl)-6, 8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-(Trifluoromethoxy)benzyl)-6, 8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Ethoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(3,5-Difluoro-4-methoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3,4-Dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-methyl-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-Benzyl-6-(4-chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-(cyclopropylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2-(((2 S, 6R)-2,6-Dimethylmorpholino)methyl)-4-(4-methoxybenzyl)pyrazolo[1,5-c]thieno [3,2-e]pyrimidin-5(4H)-one; 6-(4-Chlorobenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-(oxetan-3-yl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-(2,2,2-trifluoroethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(Cyclopropylmethyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((3-methyloxetan-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(3-(methylthio)propyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-((2,2-Difluorobenzo [d][1,3]dioxol-5-yl)methyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-neopentyl-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(3-(methylsulfonyl)propyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyrimidin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyridin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((4-methylthiazol-5-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(1,1-Dioxidothietan-3-yl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-((1,4-Dioxan-2-yl)methyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((5-oxotetrahydrofuran-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(4-Fluorobenzyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(2-Fluorobenzyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 11,11-Difluoro-6-(4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 11,11-Difluoro-6-(4-methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 6-(4-Methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 6-(4-Methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 6-(4-Methoxybenzyl)-9-(pyridin-2-ylmethyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 6-(4-Methoxybenzyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(1,1-Difluoropropan-2-yl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(4-Chlorobenzyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(4-Chlorobenzyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Benzyl-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(3-Chlorobenzyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 11,11-Difluoro-6-(2-fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-(pyrazine-2-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-(cyclopropanecarbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(Cyclopropanecarbonyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(2,2-Difluorocyclopropanecarbonyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(1-methylpyrrolidine-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-(cyclopropanecarbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 11,11-Difluoro-6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(Cyclopropanecarbonyl)-6-(2-fluoro-4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; (R)-6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; (R)-6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 9-(Cyclopropanecarbonyl)-6-(4-Methoxybenzyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 8-(Cyclopropanecarbonyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Benzoyl-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(3-Chlorobenzoyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(4-Chlorobenzoyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyridin-2-yl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(morpholin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyrrolidine-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,4′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(piperidin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((4-(pyridin-4-yloxy)piperidin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-(2-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-(3-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((3-phenoxypyrrolidin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((3-(2-Fluorophenoxy)azetidin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((4-morpholinopiperidin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((1,1-Difluoro-5-azaspiro[2.4]heptan-5-yl)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Acetyl-1,4-diazepan-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((1,4-Oxazepan-4-yl)methyl)-6-(2,3-difluoro-4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-((3-(Hydroxymethyl)-3-isobutylpiperidin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((2,2-Dimethyltetrahydro-2H-pyran-4-yl)(ethyl)amino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-((Ethyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Ethyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2,3-Difluoro-4-methoxybenzyl)-8-(((2R,6S)-2,6-dimethylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(3-fluoro-4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(2-fluoro-4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((methyl(tetrahydro-2H-pyran-4-yl)amino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chloro-4-fluorobenzyl)-8-(((2R,6S)-2,6-dimethylmorpholino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((1,1-Dioxidothiomorpholino)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Fluoro-4-methoxybenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-8-(morpholinomethyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chloro-4-fluorobenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2,3-Difluoro-4-methoxybenzyl)-8-((methyl((3-methyloxetan-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((((3-methyloxetan-3-yl)methyl)amino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2,3-Difluoro-4-methoxybenzyl)-8-((3-hydroxyazetidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-8-((3-hydroxyazetidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2,3-Difluoro-4-methoxybenzyl)-8-((dimethylamino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-((Diisopropylamino)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-10-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,4′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 11,11-Difluoro-9-isobutyl-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 11,11-Difluoro-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; and pharmaceutically acceptable salts thereof.
 23. A pharmaceutical composition comprising an effective amount of a chemical entity of Formula (I):

wherein: X is —CH— or —N—; Y is —O— or —S—; M is 0-5; R¹ is each independently selected from the group consisting of H, halo, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₁₋₆thioalkyl, —C₁₋₆alkoxy, —C₁₋₆haloalkoxy, —SO₂C₁₋₆alkyl, aryl, heteroaryl, and heterocycloalkyl; R³ and R⁴ are each independently selected from the group consisting of —H, halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —CH₂OH, —C₁₋₆alkoxy, —C₁₋₆haloalkoxy, aryl, optionally substituted 5 or 6 membered heteroaryl, —(C₁-C₆alkyl)aryl, —(C₁-C₆ alkyl)heteroaryl, and —(CR¹⁰R¹¹)₁₃NR¹²R¹³; or R³ and R⁴ taken together with the carbons to which they are attached form a saturated or unsaturated monocylic ring system, having the following structure:

D is —O—, —N(R⁹)—, or a bond; m and n are each independently 0-4, with the proviso that the sum of m and n is 1-5 when D is —O—, —N(R⁹)—, or is 2-6 when D is a bond; and with the proviso that when D is a bond, R¹ is not —Cl in the para position; R⁵, R⁶, R⁷, R⁸, are each independently selected from the group consisting of —H, —F, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —OH, —C₁₋₆alkoxy, —C₁₋₆haloalkoxy; R⁹ is selected from the group consisting of —H, —C₁₋₆alkyl, —C₁₋₆thioalkyl, —C₁₋₆haloalkyl, —CO₂C₁₋₆alkyl, —SO₂(C₁₋₆alkyl), —C₁₋₆alkyl(aryl), —C₁₋₆alkyl(C₃₋₆cycloalkyl), —C₁₋₆alkyl(heterocycloalkyl), —C₁₋₆alkyl(heteroaryl), heteroaryl, —CO(aryl), —CO(heteroaryl), —CO(heterocycloalkyl), —CO(C₃₋₆cycloalkyl), wherein each aryl, cycloalkyl, heterocycloalkyl, heteroaryl are optionally unsubstituted or substituted with a member each independently selected from the group consisting of —H, —Cl, —F, and —CH₃; R¹⁰ and R¹¹ are each independently selected from the group consisting of —H, —F, —C₁₋₆alkyl, —CF₃, and —OH; R¹² and R¹³ are each independently selected from the group consisting of —H, —C₁₋₆ alkyl, —C₃₋₆cycloalkyl, —C₁₋₆alkyl(aryl), —C₁₋₆alkyl(heteroaryl), —C₁₋₆alkyl(heterocycloalkyl), —CH₂CON(C₁₋₆alkyl)₂; or R¹² and R¹³ are taken together with the nitrogen to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more R¹⁴, where each R¹⁴ is independently selected from the group consisting of —H, —C₁₋₆alkyl, —CH₂OH, —OH, —COCH₃, —SO₂CH₃, —O-pyridyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, —O-phenyl, —O-(2-fluorophenyl), -morpholino, 1,1-difluoro-cyclopropyl, or two R¹⁴ members are taken together to form a —C₃₋₆heterocycloalkyl; and wherein the chemical entity is selected from the group consisting of compounds of Formula (I), and pharmaceutically acceptable salts of compounds of Formula (I).
 24. A pharmaceutical composition comprising an effective amount of a compound of claim 22; and a pharmaceutically acceptable excipient.
 25. A compound of Formula I:

or pharmaceutically acceptable salt thereof, wherein: X is —CH— or —N—; Y is —O— or —S—; M is 0-5; R¹ is each independently selected from the group consisting of: H, halo, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₁₋₆thioalkyl, —C₁₋₆alkoxy, —C₁₋₆haloalkoxy, —SO₂C₁₋₆alkyl, aryl, heteroaryl, and heterocycloalkyl; R³ and R⁴ are each independently selected from the group consisting of —H, halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —CH₂OH, —C₁₋₆alkoxy, —C₁₋₆haloalkoxy, aryl, optionally substituted 5 or 6 membered heteroaryl, —(C₁-C₆alkyl)aryl, —(C₁-C₆ alkyl)heteroaryl, and —(CR¹⁰R¹¹)₁₋₃NR¹²R¹³; or R³ and R⁴ taken together with the carbons to which they are attached form a saturated or unsaturated monocylic ring system, having the following structure:

D is —O—, —N(R⁹)—, or a bond; m and n are each independently 0-4, with the proviso that the sum of m and n is 1-5 when D is —O—, —N(R⁹)—, or is 2-6 when D is a bond; and with the proviso that when D is a bond, R¹ is not —Cl in the para position; R⁵, R⁶, R⁷, R⁸, are each independently selected from the group consisting of —H, —F, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —OH, —C₁₋₆alkoxy, —C₁₋₆haloalkoxy; R⁹ is selected from the group consisting of —H, —C₁₋₆alkyl, —C₁₋₆thioalkyl, —C₁₋₆haloalkyl, —CO₂C₁₋₆alkyl, —SO₂(C₁₋₆alkyl), —C₁₋₆alkyl(aryl), —C₁₋₆alkyl(C₃₋₆cycloalkyl), —C₁₋₆alkyl(heterocycloalkyl), —C₁₋₆alkyl(heteroaryl), heteroaryl, —CO(aryl), —CO(heteroaryl), —CO(heterocycloalkyl), —CO(C₃₋₆cycloalkyl), wherein each aryl, cycloalkyl, heterocycloalkyl, heteroaryl are optionally unsubstituted or substituted with a member each independently selected from the group consisting of —H, —Cl, —F, and —CH₃; R¹⁰ and R¹¹ are each independently selected from the group consisting of —H, —F, —C₁₋₆alkyl, —CF₃ and —OH; R¹² and R¹³ are each independently selected from the group consisting of —H, —C₁₋₆ alkyl, —C₃₋₆cycloalkyl, —C₁₋₆alkyl(aryl), —C₁₋₆alkyl(heteroaryl), —C₁₋₆alkyl(heterocycloalkyl), —CH₂CON(C₁₋₆alkyl)₂; or R¹² and R¹³ are taken together with the nitrogen to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more R¹⁴, where each R¹⁴ is independently selected from the group consisting of: —H, —C₁₋₆alkyl, —CH₂OH, —OH, —COCH₃, —SO₂CH₃, —O-pyridyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, —O-phenyl, —O-(2-fluorophenyl), -morpholino, 1,1-difluoro-cyclopropyl, or two R¹⁴ members are taken together to form a —C₃₋₆heterocycloalkyl.
 26. A compound selected from the group consisting of: 6-(2-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-Benzyl-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Benzyl-6-(2-chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Benzyl-6-(3-chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chlorobenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-Benzyl-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chlorobenzyl)-8-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6, 8-Dibenzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)-8-benzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Benzyl-6-(4-chlorobenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-Benzylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-Benzyl-8-isopentylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-8,9-dimethylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((1,4-Oxazepan-4-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Dimethylamino)methyl)-6-(4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-(morpholinomethyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((4-methylpiperazin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Ethyl-3-oxopiperazin-1-yl)methyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((2,2-dimethylmorpholino)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(2-oxa-5-azabicyclo [2.2.1]heptan-5-ylmethyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(7-oxa-2-azaspiro [3.5]nonan-2-ylmethyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(2-Oxa-7-azaspiro [3.5]nonan-7-ylmethyl)-6-(4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 7-((6-(4-Methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-8-yl)methyl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3 (5H)-one; 6-(4-Methoxybenzyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(3,5-Dimethylisoxazol-4-yl)-6-(4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-(pyrrolidin-1-ylmethyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-(morpholinomethyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Dimethylamino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Cyclopropyl(methyl)amino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Hydroxypiperidin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Benzyl(2-hydroxyethyl)amino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-(piperazin-1-ylmethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((((3-methyloxetan-3-yl)methyl)amino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Acetylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-(((pyridin-3-ylmethyl)amino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((3-oxopiperazin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((methyl((tetrahydrofuran-2-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(Isoindolin-2-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Cyclopropylamino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; (S)-6-(4-Methoxybenzyl)-8-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((methyl((tetrahydrofuran-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2-(((6-(4-Methoxybenzyl)-9-methyl-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-8-yl)methyl)(methyl)amino)-N,N-dimethylacetamide; 8-((1,4-Oxazepan-4-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((4-methylpiperazin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Isopropylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(2-Oxa-5-azabicyclo [2.2.1]heptan-5-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Ethyl-3-oxopiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(8-Oxa-3-azabicyclo [3.2.1]octan-3-ylmethyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((2-Ethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((2,2-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((2-methylmorpholino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((3-methylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((3R,5 S)-3,5-Dimethylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((3,4-Dimethylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-methyl-8-((3,3,4-trimethylpiperazin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; (S)-8-((Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-6-(4-methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Bromo-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(Hydroxymethyl)-6-(4-methoxybenzyl)-9-methylthieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-8,9-dimethylfuro[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; tert-Butyl 6-(4-methoxybenzyl)-5-oxo-5,6,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9(8H)-carboxylate; 6-(2-Chlorobenzyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 4-(4-Methoxybenzyl)-2-(morpholinomethyl)pyrazolo[1,5-c]thieno [3,2-e]pyrimidin-5(4H)-one; 6-(4-Chlorobenzyl)-10,10-dimethyl-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-Benzyl-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chlorobenzyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-([1,1′-Biphenyl]-4-ylmethyl)-8,9,10,11-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Methylbenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-(Trifluoromethyl)benzyl)-6, 8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Methoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(3,4-Dichlorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Fluorobenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Chloro-3-fluorobenzyl)-6, 8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Chloro-2-fluorobenzyl)-6, 8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(3-Fluoro-4-methoxybenzyl)-6, 8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-(Trifluoromethoxy)benzyl)-6, 8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Ethoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(3,5-Difluoro-4-methoxybenzyl)-6,8,10,11-tetrahydro-5H-pyrano[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one; 6-(4-Chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3,4-Dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-methyl-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-Benzyl-6-(4-chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-(cyclopropylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 2-(((2 S, 6R)-2,6-Dimethylmorpholino)methyl)-4-(4-methoxybenzyl)pyrazolo[1,5-c]thieno [3,2-e]pyrimidin-5(4H)-one; 6-(4-Chlorobenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-(oxetan-3-yl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-(2,2,2-trifluoroethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(Cyclopropylmethyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((3-methyloxetan-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(3-(methylthio)propyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-((2,2-Difluorobenzo [d][1,3]dioxol-5-yl)methyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-neopentyl-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(3-(methylsulfonyl)propyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyrimidin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyridin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((4-methylthiazol-5-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(1,1-Dioxidothietan-3-yl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-((1,4-Dioxan-2-yl)methyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((5-oxotetrahydrofuran-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(4-Fluorobenzyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(2-Fluorobenzyl)-6-(4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 11,11-Difluoro-6-(4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 11,11-Difluoro-6-(4-methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-(pyridin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((tetrahydrofuran-3-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 6-(4-Methoxybenzyl)-9-((1-methyl-1H-imidazol-2-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 6-(4-Methoxybenzyl)-9-(pyrimidin-2-ylmethyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 6-(4-Methoxybenzyl)-9-(pyridin-2-ylmethyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 6-(4-Methoxybenzyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((tetrahydro-2H-pyran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((tetrahydrofuran-3-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(1,1-Difluoropropan-2-yl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(4-Chlorobenzyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(4-Chlorobenzyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Benzyl-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(3-Chlorobenzyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 11,11-Difluoro-6-(2-fluoro-4-methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-(pyrazine-2-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chlorobenzyl)-9-(cyclopropanecarbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(Cyclopropanecarbonyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(2,2-Difluorocyclopropanecarbonyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(1-methylpyrrolidine-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-(cyclopropanecarbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Chloro-2-fluorobenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 11,11-Difluoro-6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-(Cyclopropanecarbonyl)-6-(2-fluoro-4-methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; (R)-6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; (R)-6-(4-Methoxybenzyl)-9-(tetrahydrofuran-3-carbonyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 9-(Cyclopropanecarbonyl)-6-(4-Methoxybenzyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 8-(Cyclopropanecarbonyl)-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-(tetrahydrofuran-3-carbonyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-Benzoyl-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(3-Chlorobenzoyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(4-Chlorobenzoyl)-6-(3,4-dimethoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyridin-2-yl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(morpholin-2-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-(pyrrolidine-3-carbonyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,4′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; and 6-(4-Methoxybenzyl)-9-(piperidin-4-ylmethyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one, and pharmaceutically acceptable salts thereof.
 27. A compound selected from the group consisting of: 6-(4-Methoxybenzyl)-8-((4-(pyridin-4-yloxy)piperidin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-(2-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-(3-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-(4-Fluorophenyl)piperazin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((3-phenoxypyrrolidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((3-(2-Fluorophenoxy)azetidin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((4-morpholinopiperidin-1-yl)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((1,1-Difluoro-5-azaspiro[2.4]heptan-5-yl)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((4-Acetyl-1,4-diazepan-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((1,4-Oxazepan-4-yl)methyl)-6-(2,3-difluoro-4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-((3-(Hydroxymethyl)-3-isobutylpiperidin-1-yl)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((2,2-Dimethyltetrahydro-2H-pyran-4-yl)(ethyl)amino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-((Ethyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((Ethyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)-6-(4-Methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2,3-Difluoro-4-methoxybenzyl)-8-(((2R,6S)-2,6-dimethylmorpholino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(3-fluoro-4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(2-fluoro-4-methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-9-((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((methyl(tetrahydro-2H-pyran-4-yl)amino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chloro-4-fluorobenzyl)-8-(((2R,6S)-2,6-dimethylmorpholino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 8-((1,1-Dioxidothiomorpholino)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Fluoro-4-methoxybenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-8-(morpholinomethyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(3-Chloro-4-fluorobenzyl)-8-(morpholinomethyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2,3-Difluoro-4-methoxybenzyl)-8-((methyl((3-methyloxetan-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-8-((((3-methyloxetan-3-yl)methyl)amino)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2,3-Difluoro-4-methoxybenzyl)-8-((3-hydroxyazetidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2-Fluoro-4-methoxybenzyl)-8-((3-hydroxyazetidin-1-yl)methyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(2,3-Difluoro-4-methoxybenzyl)-8-((dimethylamino)methyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 9-((Diisopropylamino)methyl)-6-(4-Methoxybenzyl)thieno [3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-10-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[3′,4′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 6-(4-Methoxybenzyl)-6,8,9,10,11,12-hexahydro-5H-[1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-5-one; 11,11-Difluoro-9-isobutyl-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; 11,11-Difluoro-6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one; and 6-(4-Methoxybenzyl)-8,9,10,11-tetrahydropyrido[3′,2′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one, and pharmaceutically acceptable salts thereof. 